Potassium channel modulators

ABSTRACT

This invention relates to novel compounds useful as potassium channel modulators. More specifically the invention provides chemical compounds useful as modulators of SK Ca  and/or IK Ca  channels.

TECHNICAL FIELD

This invention relates to novel compounds useful as potassium channelmodulators. More specifically the invention provides chemical compoundsuseful as modulators of SK_(Ca) and/or IK_(Ca) channels.

BACKGROUND ART

Ion channels are transmembrane proteins, which catalyse the transport ofinorganic ions across cell membranes. The ion channels participate inprocesses as diverse as the generation and timing of action potentials,synaptic transmissions, secretion of hormones, contraction of muscles,etc.

Two types of Ca²⁺-activated potassium channels have been described fromlymphocytes: 1) Small-conductance, apamin-sensitive, Ca²⁺-activatedK-channels (SK_(Ca)) and 2) Intermediate-conductance, inwardlyrectifying, Clotrimazole-sensitive, Ca²⁺-activated K-channels (IK_(Ca)),also referred to as Gardos-channels.

WO 97/34589 describes triaryl methane compounds that inhibit mammaliancell proliferation, inhibit the Gardos channel of erythrocytes, reducesickle erythrocyte dehydration and/or delay the occurrence oferythrocyte sickling or deformation, and suggest the use of thesecompounds in abnormal cell proliferation.

WO 97/34599 describes the use of Clotrimazol and related compounds inthe treatment of diarrhoea.

WO 00/50026 describes Gardos channel antagonists (i.e. Ca²⁺-activatedK-channels), which inhibit the Gardos channel of erythrocytes, reducesickle erythrocyte dehydration and/or delay the occurrence oferythrocyte sickling or deformation.

WO 01/27070 describes the use of carbonylamino derivatives for treatingCNS disorders relating to metabotropic glutamate receptor antagonistsand/or agonists.

WO 01/49663 describes the use of certain substituted triarylmethanecompounds for immunosuppressive treatment of autoimmune disorders orinflammatory diseases.

SUMMARY OF THE INVENTION

According to the present invention it has now been found that aparticular group of chemical compounds possess valuable activity asmodulators of SK_(Ca) and/or IK_(Ca) channels.

In its first aspect the invention provides chemical compoundscharacterized by the general Formula I

any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, or an N-oxide thereof,

wherein

X and Y, independently of each another, represent a mono- or polycyclic,carbocyclic and/or heterocyclic group, which carbocyclic or heterocyclicgroups optionally may be substituted one or more times with alkyl,alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitroand/or cyano; and

Z represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,hydroxy-alkyl, cyano-alkyl, halo-alkyl, halo-alkenyl or halo-alkynyl,alkoxy, alkoxy-alkyl, alkoxy-alkoxy, alkoxy-alkoxy-alkyl, acyl,alkoxy-carbonyl, alkoxy-alkoxy-carbonyl, a malonic acid dialkyl ester, adiphenyl methyl group, or a mono- or polycyclic, carbocyclic orheterocyclic group, which carbocyclic or heterocyclic group optionallymay be substituted one or more times with alkyl, alkenyl, alkynyl,hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano; and

L¹ and L², independently of each another, may be absent or representdivalent alkyl, alkenyl, alkynyl, O, S or NR⁹; wherein

R⁹ represents hydrogen, alkyl, alkoxy or aryl; and

L³ may be absent or represents a linker of the formula—(CH₂)_(n)—Y—(CH₂)_(m)—,

wherein

n and m, independently of each another, represent 0, 1, 2, 3 or 4; and

Y is absent or represents O, S, NR⁹, wherein

R⁹ represents hydrogen, alkyl, alkoxy or aryl; and

D represents alkyl, cycloalkyl, alkenyl, alkynyl or haloalkyl, or agroup of the formula —R⁶—NR⁵R⁴, —R⁶—NO₂, —R⁶—OR⁴, —R⁶—SR⁴,—R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴, —R⁶—S(═O)₂R⁴, —R⁶—S(═O)₂OR⁴,—R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴, —R⁶—NR⁷S(═O)₂NR⁵R⁴, —R⁶—CN,—R⁶—C(═NR⁵)R⁴, —R⁶—C(═NNR⁵)R⁴, —R⁶—C(═NOR⁵)R⁴, —R⁶—C(═O)R⁴,—R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴, —R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴,—R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴), —R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴),—R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂, —R⁶—NR⁵C(═O)R⁴, —R⁶—NR⁷C(═O)NR⁵R⁴,—R⁶—C(═S)NR⁵R⁴, —R⁶—CH[C(═O)R⁴]₂, —R⁶——CH[C(═S)R⁴]₂, —R⁶—CH[C(═O)OR⁴]₂,—R⁶—CH[C(═S)OR⁴]₂, —R⁶—CH[C(═O)SR⁴]₂, —R⁶—CH[C(═S)SR⁴]₂ or—R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with halogen, alkyl, CF₃,nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; or

D represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, cycloalkyl, alkenyl, alkynyl, halogen,haloalkyl, aryl and heteroaryl, and/or a group of the formula —R⁶—NR⁵R⁴,—R⁶—NO₂, —R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴, —R⁶—S(═O)₂R⁴,—R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴, —R⁶—NR⁷S(═O)₂NR⁵R⁴,—R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶—C(═NNR⁵)R⁴, —R⁶—C(═NOR⁵)R⁴, —R⁶—C(═O)R⁴,—R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴, —R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴,—R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴), —R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴),—R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂, —R⁶—C(═O)NR⁵R⁴, —R⁶—NR⁵C(═O)R⁴,—R⁶—NR⁷C(═O)NR⁵R⁴, —R⁶—C(═S)NR⁵R⁴, —R⁶—CH[C(═O)R⁴]₂, —R⁶—CH[C(═S)R⁴]₂,—R⁶—CH[C(═O)OR⁴]₂, —R⁶—CH[C(═S)OR⁴]₂, —R⁶—CH[C(═O)SR⁴]₂,—R⁶—CH[C(═S)SR⁴]₂ or —R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with halogen, alkyl, CF₃,nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; or

D represents —S—R¹, —S(═O)—R¹, —S(═O)₂—R¹, —S(═O)—NR²R³, —S—C(═O)—R¹,—S—C(═O)—NR²R³, —O(C═O)—R¹, —O(C═O)—NR²R³, —N(C═O)—R¹, —N(C═O)—NR²R³,—P—(R²R³), —P(═O)—R¹, —P(═O)—(R²R³), —P(═O)₂—(R²R³); wherein

R¹ represents alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl,haloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl, which aromaticgroups may optionally be substituted once or twice with halogen, alkyl,CF₃, nitro and/or cyano; or a group of the formula —R⁶—NR⁵R⁴, —R⁶—NO₂,—R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴, —R⁶—S(═O)₂R⁴,—R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴, —R⁶—NR⁷S(═O)₂NR⁵R⁴,—R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶—C(═NNR⁵)R⁴, —R⁶—C(═NOR⁵)R⁴, —R⁶—C(═O)R⁴,—R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴, —R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴,—R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴), —R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴),—R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂, —R⁶—NR⁵C(═O)R⁴, —R⁶—NR⁷C(═O)NR⁵R⁴,—R⁶—C(═S)NR⁵R⁴, —R⁶—CH[C(═O)R⁴]₂, —R⁶—CH[C(═S)R⁴]₂, —R⁶—CH[C(═O)OR⁴]₂,—R⁶—CH[C(═S)OR⁴]₂, —R⁶—CH[C(═O)SR⁴]₂, —R⁶—CH[C(═S)SR⁴]₂ or—R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with with halogen, alkyl,CF₃, nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; and

R² and R³, independently of each another, represent hydrogen, hydroxy,alkyl or alkoxy; or

R² and R³, together with the phosphor atom to which they are bound,represent a heterocyclic ring; or

R¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, cycloalkyl, alkenyl, alkynyl, halogen,haloalkyl, aryl, heteroaryl and/or a group of the formula —R⁶—NR⁵R⁴,—R⁶NO₂, —R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴, —R⁶—S(═O)₂R⁴,—R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴, —R⁶—NR⁷S(═O)₂NR⁵R⁴,—R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶—C(═NNR⁵)R⁴, —R⁶—C(═NOR⁵)R⁴, —R⁶—C(═O)R⁴,—R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴, —R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴,—R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴), —R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴),—R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂, —R⁶—C(═O)NR⁵R⁴, —R⁶—NR⁵C(═O)R⁴,—R⁶—NR⁷C(═O)NR⁵R⁴, —R⁶—C(═S)NR⁵R⁴, —R⁶—CH[C(═O)R⁴]₂, —R⁶—CH[C(═S)R⁴]₂,—R⁶—CH[C(═O)OR⁴]₂, —R⁶—CH[C(═S)OR⁴]₂, —R⁶—CH[C(═O)SR⁴]₂,—R⁶—CH[C(═S)SR⁴]₂ or —R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with with halogen, alkyl,CF₃, nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; and

R² and R³, independently of each another, represent hydrogen, alkyl oralkoxy.

In another aspect the invention provides pharmaceutical compositionscomprising a therapeutically effective amount of a chemical compound ofthe invention, or a pharmaceutically-acceptable addition salt thereof,together with at least one pharmaceutically-acceptable carrier ordiluent.

In yet another aspect the invention relates to the use of a chemicalcompound of the invention, or a pharmaceutically-acceptable additionsalt thereof, for the manufacture of a medicament.

In still another aspect the invention provides methods for treatment,prevention or alleviation of diseases or disorders or conditionsresponsive to modulation of SK_(Ca) and/or IK_(Ca) channels, whichmethod comprises the step of administering to such a living animal bodyin need thereof a therapeutically effective amount of a compound of theinvention or a pharmaceutically-acceptable addition salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

Tertiary Triaryl Derivatives

In its first aspect the present invention provides tertiary triarylderivative of Formula I

an enantiomer or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof,

wherein

X and Y, independently of each another, represent a mono- or polycyclic,carbocyclic and/or heterocyclic group, which carbocyclic or heterocyclicgroups optionally may be substituted one or more times with alkyl,alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitroand/or cyano; and

Z represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,hydroxy-alkyl, cyano-alkyl, halo-alkyl, halo-alkenyl or halo-alkynyl,alkoxy, alkoxy-alkyl, alkoxy-alkoxy, alkoxy-alkoxy-alkyl, acyl,alkoxy-carbonyl, alkoxy-alkoxy-carbonyl, a malonic acid dialkyl ester, adiphenyl methyl group, or a mono- or polycyclic, carbocyclic orheterocyclic group, which carbocyclic or heterocyclic group optionallymay be substituted one or more times with alkyl, alkenyl, alkynyl,hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano; and

L¹ and L², independently of each another, may be absent or representdivalent alkyl, alkenyl, alkynyl, O, S or NR⁹; wherein

R⁹ represents hydrogen, alkyl, alkoxy or aryl; and

L³ may be absent or represents a linker of the formula—(CH₂)_(n)—Y—(CH₂)_(m)—, wherein

n and m, independently of each another, represent 0, 1, 2, 3 or 4; and

Y is absent or represents O, S, NR⁹, wherein

R⁹ represents hydrogen, alkyl, alkoxy or aryl; and

D represents alkyl, cycloalkyl, alkenyl, alkynyl or haloalkyl, or agroup of the formula

—R⁶—NR⁵R⁴, —R⁶—NO₂, —R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴,—R⁶—S(═O)₂R⁴, —R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴,—R⁶—NR⁷S(═O)₂NR⁵R⁴, —R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶——C(═NNR⁵)R⁴,—R⁶—C(═S)OR⁴, —R⁶—C(═O)R⁴, —R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴,—R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴, —R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴),—R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴), —R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂,—R⁶—NR⁵C(═O)R⁴, —R⁶—NR⁷C(═O)NR⁵R⁴, —R⁶—C(═S)NR⁵R⁴, —R⁶—CH[C(═O)R⁴]₂,—R⁶—CH[C(═S)R⁴]₂, —R⁶—CH[C(═O)OR⁴]₂, —R⁶—CH[C(═S)OR⁴]₂,—R⁶—CH[C(═O)SR^(4]) ₂, —R⁶—CH[C(═S)SR⁴]₂ or —R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with halogen, alkyl, CF₃,nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; or

D represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, cycloalkyl, alkenyl, alkynyl, halogen,haloalkyl, aryl and heteroaryl, and/or a group of the formula

—R⁶—NR⁵R⁴, —R⁶—NO₂, —R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴,—R⁶—S(═O)₂R⁴, —R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴,—R⁶—NR⁷S(═O)₂NR⁵R⁴, —R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶——C(═NNR⁵)R⁴,—R⁶—C(═NOR⁵)R⁴, —R⁶—C(═O)R⁴, —R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴,—R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴, —R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴),—R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴), —R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂,—R⁶——C(═O)NR⁵R⁴, —R⁶—NR⁵C(═O)R⁴, —R⁶—NR⁷C(═O)NR⁵R⁴, —R⁶—C(═S)NR⁵R⁴,—R⁶—CH[C(═O)R⁴]₂, —R⁶—CH[C(═S)R⁴]₂, —R⁶—CH[C(═O)OR⁴]₂,—R⁶—CH[C(═S)OR⁴]₂, —R⁶—CH[C(═O)SR⁴]₂, —R⁶—CH[C(═S)SR⁴]₂ or—R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with halogen, alkyl, CF₃,nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; or

D represents —S—R¹, —S(═O)—R¹, —S(═O)₂—R¹, —S(═O)—NR²R³, —S—C(═O)—R¹,—S—C(═O)—NR²R³, —O(C═O)-R¹, —O(C═O)—NR²R³, —N(C═O)—R¹, —N(C═O)—NR²R³,—P—(R²R³), —P(═O)—R¹, —P(═O)—(R²R³), —P(═O)₂—(R²R³); wherein

R¹ represents alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl,haloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl, which aromaticgroups may optionally be substituted once or twice with halogen, alkyl,CF₃, nitro and/or cyano; or a group of the formula

—R⁶—NR⁵R⁴, —R⁶—NO₂, —R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴,—R⁶—S(═O)₂R⁴, —R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴,—R⁶—NR⁷S(═O)₂NR⁵R⁴, —R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶—C(═NNR⁵)R⁴,—R⁶—C(═NOR⁵)R⁴, —R⁶—C(═O)R⁴, —R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴,—R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴, —R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴),—R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴), —R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂,—R⁶—NR⁵C(═O)R⁴, —R⁶—NR⁷C(═O)NR⁵R⁴, —R⁶—C(═S)NR⁵R⁴, —R⁶—CH[C(═O)R⁴]₂,—R⁶—CH[C(═S)R⁴]₂, —R⁶—CH[C(═O)OR⁴]₂, —R⁶—CH[C(═S)OR⁴]₂,—R⁶—CH[C(═O)SR⁴]₂, —R⁶—CH[C(═S)SR⁴]₂, or —R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with with halogen, alkyl,CF₃, nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; and

R² and R³, independently of each another, represent hydrogen, hydroxy,alkyl or alkoxy; or

R² and R³, together with the phosphor atom to which they are bound,represent a heterocyclic ring; or

R¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, cycloalkyl, alkenyl, alkynyl, halogen,haloalkyl, aryl, heteroaryl and/or a group of the formula

—R⁶—NR⁵R⁴, —R⁶—NO₂, —R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴,—R⁶—S(═O)₂R⁴, —R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂—NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴,—R⁶—NR⁷S(═O)₂NR⁵R⁴, —R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶—C(═NNR⁵)R⁴,—R⁶—C(═NOR⁵)R⁴, —R⁶—C(═O)R⁴, —R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴,—R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴, —R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴),—R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴), —R⁶—C(═S)NR⁵(SR⁴), —⁶—CH(CN)₂,—R⁶—C(═O)NR⁵R⁴, —R⁶—NR⁵C(═O)R⁴, —R⁶—NR⁷—C(═O)NR⁵R⁴, —R⁶—C(═S)NR⁵R⁴,—R⁶—CH[C(═O)R⁴]₂, —R⁶—CH[C(═S)R⁴]₂, —R⁶—CH[C(═O)OR⁴]₂,—R⁶—CH[C(═S)OR⁴]₂, —R⁶—CH[C(═O)SR⁴]₂, —R⁶—CH[C(═S)SR⁴]₂ or—R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with with halogen, alkyl,CF₃, nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; and

R² and R³, independently of each another, represent hydrogen, alkyl oralkoxy.

In a more preferred embodiment

L¹ and L² are absent; and

L³ is absent or represents a linker of the formula —Y—, wherein

Y represents O, S or NR⁹, wherein

R⁹ represents hydrogen or alkyl; and

D represents —S—R¹, —S(═O)—R¹, —S(═O)₂—R¹, —S(═O)—NR²R³, —S—C(═O)—R¹,—S—C(═O)—NR²R³, —O(C═O)—R¹, —O(C═O)—NR²R³, —N(C═O)—R¹, —N(C═O)—NR²R³,—P—(R¹)₂, —P(R²R³), —P(═O)—R¹, —P(═O)—(R²R³), —P(═O)₂—(R¹)₂ or—P(═O)—(OR¹)₂; wherein

R¹ represents alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl,haloalkyl, or a group of the formula

—R⁶—NR⁵R⁴, —R⁶—NO₂, —R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴,—R⁶—S(═O)₂R⁴, —R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴,—R⁶—NR⁷S(═O)₂NR⁵R⁴, —R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶—C(═NNR⁵)R⁴,—R⁶—C(═NOR⁵)R⁴, —R⁶—C(═O)R⁴, —R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴,—R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴, —R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴),—R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴), —R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂,—R⁶—NR⁵C(═O)R⁴, —R⁶—NR⁷C(═O)NR⁵R⁴, —R⁶—C(═S)NR⁵R⁴, —R⁶—CH[C(═O)R⁴]₂,—R⁶—CH[C(═S)R⁴]₂, —R⁶—CH[C(═O)OR⁴]₂, —R⁶—CH[C(═S)OR⁴]₂,—R⁶—CH[C(═O)SR⁴]₂, —R⁶—CH[C(═S)SR⁴]₂ or —R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with with halogen, alkyl,CF₃, nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R⁶ is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; and

R² and R³, independently of each another, represent hydrogen, hydroxy,alkyl or alkoxy; or

R² and R³, together with the phosphor atom to which they are bound,represent a heterocyclic ring; or

R¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, cycloalkyl, alkenyl, alkynyl, halogen,haloalkyl, aryl, heteroaryl and/or a group of the formula

—R⁶—NR⁵R⁴, —R⁶—NO₂, —R⁶—OR⁴, —R⁶—SR⁴, —R⁶—S(═O)NR⁵R⁴, —R⁶—S(═O)R⁴,—R⁶—S(═O)₂R⁴, —R⁶—S(═O)₂OR⁴, —R⁶—S(═O)₂NR⁵R⁴, —R⁶—NR⁵S(═O)₂R⁴,—R⁶—NR⁷S(═O)₂NR⁵R⁴, —R⁶—CN, —R⁶—C(═NR⁵)R⁴, —R⁶—C(═NNR⁵)R⁴,—R⁶—C(═NOR⁵)OR⁴, —R⁶—C(═O)R⁴, —R⁶—C(═O)NR⁵R⁴, —R⁶—C(═S)R⁴, —R⁶—C(═O)OR⁴,—R⁶—C(═S)OR⁴, —R⁶—C(═O)SR⁴, —R⁶—C(═S)SR⁴, —R⁶—C(═O)NR⁵(OR⁴),—R⁶—C(═S)NR⁵(OR⁴), —R⁶—C(═O)NR⁵(SR⁴), —R⁶—C(═S)NR⁵(SR⁴), —R⁶—CH(CN)₂,—R⁶—C(═O)NR⁵R⁴, —R⁶—NR⁵C(═O)R⁴, —R⁶—NR⁷C(═O)NR⁵R⁴, —R⁶—C(═S)NR⁵R⁴,—R⁶—CH[C(═O)R⁴]₂, —R⁶—CH[C(═S)R⁴]₂, —R⁶—CH[C(═O)OR⁴]₂,—R⁶—CH[C(═S)OR⁴]₂, —R⁶—CH[C(═O)SR⁴]₂, —R⁶—CH[C(═S)SR⁴]₂ or—R⁶—CH[C(═S)NR⁵R⁴]₂; wherein

R⁴, R⁵ and R⁷, independently of each another, represent hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, which aromatic groupmay optionally be substituted once or twice with halogen, alkyl, CF₃,nitro and/or cyano; or

R⁴ and R⁵, together with the atoms to which they are bound, form aheterocyclic ring, and R⁷ is as defined above; and

R is absent or represents a linker selected from alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl; and

R² and R³, independently of each another, represent hydrogen or alkyl.

In a yet more preferred embodiment,

X, Y and Z represent a phenyl group, which phenyl groups, independentlyof each another, are optionally substituted one or more times withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano; or

X and Y represent a phenyl group, which phenyl groups, independently ofeach another, are optionally substituted one or more times with alkyl,alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitroand/or cyano; and

Z represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,hydroxy-alkyl, cyano-alkyl, halo-alkyl, halo-alkenyl, halo-alkynyl,alkoxy, alkoxy-alkyl, alkoxy-alkoxy, alkoxy-alkoxy-alkyl, acyl,alkoxy-carbonyl, alkoxy-alkoxy-carbonyl, a malonic acid dialkyl ester ora diphenyl methyl group; or

X and Y represent a phenyl group, which phenyl groups, independently ofeach another, are optionally substituted one or more times with alkyl,alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitroand/or cyano; and

Z represents a heteroaryl group, which heteroaryl is optionallysubstituted one or more times with alkyl, alkenyl, alkynyl, hydroxy,alkoxy, amino, halogen, haloalkyl, nitro and/or cyano; or

one of X and Y represents a phenyl group, which phenyl group isoptionally substituted one or more times with alkyl, alkenyl, alkynyl,hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano; and

the other of X and Y represents a heteroaryl group, which heteroaryl isoptionally substituted one or more times with alkyl, alkenyl, alkynyl,hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano; and

Z represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,hydroxy-alkyl, cyano-alkyl, halo-alkyl, halo-alkenyl, halo-alkynyl,alkoxy, alkoxy-alkyl, alkoxy-alkoxy, alkoxy-alkoxy-alkyl, acyl,alkoxy-carbonyl, alkoxy-alkoxy-carbonyl, a malonic acid dialkyl ester ora diphenyl methyl group; or

one of X and Y represents a phenyl group, which phenyl group isoptionally substituted one or more times with alkyl, alkenyl, alkynyl,hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano; and

Z and the other of X and Y represents a heteroaryl group, whichheteroaryl is optionally substituted one or more times with alkyl,alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitroand/or cyano.

In an even more preferred embodiment, the heteroaryl group is thiazolyl,in particular 2, 4 or 5-thiazolyl; isothiazolyl, in particular 3, 4 or5-isothiazolyl; imidazolyl, in particular 1, 2 or 4-imidazolyl;oxazolyl, in particular 2, 4 or 5-oxazolyl; isoxazolyl, in particular 3,4 or 5-isoxazolyl; pyridinyl, in particular 2, 3 or 4-pyridinyl;pyrimidinyl, in particular 2, 4 or 5-pyrimidinyl; pyrrolyl (azolyl), inparticular 1, 2 or 3-pyrrolyl, [1,3,2]dioxaphospholane or[1,3,2]dioxaphosphinane.

In a still more preferred embodiment

X, Y and Z represent a phenyl group, which phenyl groups, independentlyof each another, optionally are substituted one or more times withhalogen, in particular fluoro and/or chloro; alkyl, in particularmethyl, ethyl, propyl and/or isopropyl; haloalkyl, in particular CF₃;nitro and/or cyano; or

X and Y represent a phenyl group, which phenyl groups, independently ofeach another, optionally are substituted one or more times with halogen,in particular fluoro and/or chloro; alkyl, in particular methyl, ethyl,propyl and/or isopropyl; haloalkyl, in particular CF₃; nitro and/orcyano; and

Z represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,hydroxy-alkyl, cyano-alkyl, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,alkoxy-alkoxy-alkyl, acyl, alkoxy-carbonyl, malonic acid dialkyl esteror a diphenyl methyl group; or

X and Y represent a phenyl group, which phenyl groups, independently ofeach another, optionally are substituted one or more times with halogen,in particular fluoro and/or chloro; alkyl, in particular methyl, ethyl,propyl and/or isopropyl; haloalkyl, in particular CF₃; nitro and/orcyano; and

Z represents 2-thiazolyl, 4-thiazolyl, 2-imidazolyl, 2-oxazolyl,2-pyridinyl or [1,3,2]dioxaphospholane, which aromatic groups may besubstituted one or more times with halogen, in particular fluoro and/orchloro; alkyl, in particular methyl, ethyl, propyl and/or isopropyl;haloalkyl, in particular CF₃; nitro and/or cyano; or

one of X and Y represents a phenyl group, which phenyl group isoptionally substituted one or more times with halogen, in particularfluoro and/or chloro; alkyl, in particular methyl, ethyl, propyl and/orisopropyl; haloalkyl, in particular CF₃; nitro and/or cyano; and

the other of X and Y represents 2-thiazolyl, 4-thiazolyl, 2-imidazolyl,2-oxazolyl, 2-pyridinyl or [1,3,2]dioxaphospholane, which aromaticgroups may be substituted one or more times with halogen, in particularfluoro and/or chloro; alkyl, in particular methyl, ethyl, propyl and/orisopropyl; haloalkyl, in particular CF₃; nitro and/or cyano; and

Z represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,hydroxy-alkyl, cyano-alkyl, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,alkoxy-alkoxy-alkyl, acyl, alkoxy-carbonyl, malonic acid dialkyl esteror a diphenyl methyl group; or

one of X and Y represents a phenyl group, which phenyl group isoptionally substituted one or more times with halogen, in particularfluoro and/or chloro; alkyl, in particular methyl, ethyl, propyl and/orisopropyl; haloalkyl, in particular CF₃; nitro and/or cyano; and

Z and the other of X and Y represents 2-thiazolyl, 4-thiazolyl,2-imidazolyl, 2-oxazolyl, 2-pyridinyl or [1,3,2]dioxaphospholane, whicharomatic groups may be substituted one or more times with halogen, inparticular fluoro and/or chloro; alkyl, in particular methyl, ethyl,propyl and/or isopropyl; haloalkyl, in particular CF₃; nitro and/orcyano.

In a still more preferred embodiment

D represents a phenyl group, which phenyl groupis substituted once ortwice with halogen, in particular fluoro and/or chloro; alkyl, inparticular methyl, ethyl, propyl and/or isopropyl; haloalkyl, inparticular CF₃; nitro and/or cyano; or

D represents a heteroaryl group selected from 2-thiazolyl, 4-thiazolyl,2-imidazolyl, 2-oxazolyl or 2-pyridinyl, which heteroaryl group may besubstituted once or twice with halogen, in particular fluoro and/orchloro; alkyl, in particular methyl, ethyl, propyl and/or isopropyl;haloalkyl, in particular CF₃; hydroxy, nitro and/or cyano; and

L³ is absent or represents a linker of the formula —Y—, wherein

Y represents O or S.

In a still more preferred embodiment the phenyl groups and/or theheteroaryl groups are substituted once or twice with fluoro, chloro,CF₃, nitro and/or cyano.

In a most preferred embopdiment the compound of the invention is

2-[Bis-(4-fluoro-phenyl)-(4-nitro-3-trifluoromethyl-phenoxy)-methyl]-thiazole;

2-[Tris-(4-fluoro-phenyl)-methylsulfanyl]-pyridin-1-ol;

1-Methyl-2-[tris-(4-fluoro-phenyl)-methylsulfanyl]-1H-imidazole;

2-[Tris-(4-fluoro-phenyl)-methylsulfanyl]-pyridine;

2-[(2-Fluoro-phenyl)-bis-(4-fluoro-phenyl)-methoxy]-[1,3,2]-dioxaphospholane;or

2-[Tris-(4-fluoro-phenyl)-methoxy]-[1,3,2]-dioxaphospholane;

any of its enantiomers or any mixture of enantiomers, or apharmaceutically acceptable salt thereof, or an N-oxide thereof.

In a still more preferred embodiment

D represents —CN, R⁶—CN, —CON(R²R³), —S—R¹, —S(═O)—R¹, —S(═O)₂—R¹,—S—C(═O)—R¹, —O(C═O)—R¹, —P—(R²R³), —P(═O)(R²R³), —P(═O)₂(R²R³); wherein

R¹ represents alkyl, cycloalkyl, cycloalkyl-alkyl or —NR⁵R⁴; wherein

R⁴ and R⁵, independently of each another, represent hydrogen, alkyl,cycloalkyl, aryl or heteroaryl, which aromatic group may optionally besubstituted once or twice with halogen, alkyl, CF₃, nitro and/or cyano;or

R⁴ and R⁵, together with the N atom to which they are bound, form apyrrolidine or piperidine ring; or

R¹ represents aryl, aralkyl, heteroaryl, heteroaryl-alkyl, whicharomatic groups may optionally be substituted once or twice withhalogen, alkyl, CF₃, nitro and/or cyano; and

R² and R³, independently of each another, represent hydrogen, alkyl oralkoxy; or

R² and R³, together with the phosphor atom to which they are bound,represent a heterocyclic ring selected from [1,3,2]dioxaphospholane and[1,3,2]dioxaphosphinane; and

R⁶ is absent or represents alkyl.

In a still more preferred embodiment

L³ is absent or represents —O— or —S—.

In a still more preferred embodiment X and Y represent a phenyl group,which phenyl groups, independently of each another, optionally aresubstituted one or more times with halogen, in particular fluoro and/orchloro; alkyl, in particular methyl, ethyl, propyl and/or isopropyl;haloalkyl, in particular CF₃; nitro and/or cyano;

Z represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,hydroxy-alkyl, cyano-alkyl, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,alkoxy-alkoxy-alkyl, acyl, alkoxy-carbonyl, malonic acid dialkyl esteror a diphenyl methyl group; and

D represents —CN, R⁶—CN, —CON(R²R³), wherein

R² and R³, independently of each another, represent hydrogen or alkyl;and

R⁶ represents alkyl.

In a most preferred embodiment compound of the invention is

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-enenitrile;

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-3-methyl-butyronitrile;

2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyronitrile;

2,2-Bis-(4-fluoro-phenyl)-4-methyl-pentanenitrile;

2,2-Bis-(4-fluoro-phenyl)-pent-4-enenitrile;

2,2-Bis-(4-fluoro-phenyl)-pent-4-ynenitrile;

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-ynenitrile;

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-4-methyl-pentanenitrile;

2,2-Bis-(4-fluoro-phenyl)-3,3-diphenyl-propionitrile;

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-3,3-diphenyl-propionitrile;

2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-3-methyl-butyronitrile;

2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-4-methyl-pentanenitrile;

2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-enenitrile;

2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-ynenitrile;

2,2-Bis-(4-fluoro-phenyl)-3-oxo-butyronitrile;

3-Ethoxy-2-(4-fluoro-phenyl)-2-(2-fluoro-phenyl)-propionitrile;

3-Cyano-3-(4-fluoro-phenyl)-3-(2-fluoro-phenyl)-propionic acid ethylester;

3-Ethoxy-2,2-bis-(4-fluoro-phenyl)-propionitrile;

3-Cyano-3,3-bis-(4-fluoro-phenyl)-propionic acid ethyl ester;

Cyano-(4-fluoro-phenyl)-(2-fluoro-phenyl)-acetic acid methyl ester;

2-[Cyano-bis-(4-fluoro-phenyl)-methyl]-malonic acid diethyl ester;

2,2-Bis-(4-fluoro-phenyl)-4-hydroxy-butyronitrile;

2,2-Bis-(4-fluoro-phenyl)-3-(2-methoxy-ethoxy)-propionitrile;

2,2-Bis-(4-fluoro-phenyl)-succinonitrile; or

2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyramide;

any of its enantiomers or any mixture of enantiomers, or apharmaceutically acceptable salt thereof, or an N-oxide thereof.

In a second preferred embodiment, the chemical compound of the inventionis represented by the following Formula IV (Type 4)

wherein

m is 0, 1 or 2;

n is 0, 1 or 2;

X and Y, independently of each another, represent alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;

Ar¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino,halogen, haloalkyl, nitro and/or cyano; and

R represents a group (Ar²) which is a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen or alkyl;or

R¹ and R², together with the N atom to which they are bound, form a 5-to 7-membered heterocyclic ring.

In a more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano; or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen or alkyl;or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or a piperidine ring.

In a yet more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents phenyl, which may be substituted once or twice withhalogen, alkyl, CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with halogen, alkyl, CF₃, nitroand/or cyano; or

R represents alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl or halo-alkyl;and

R¹ and R², independently of each another, represent hydrogen or alkyl;or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or a piperidine ring.

In a still more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, chloro, CF₃,nitro and/or cyano;

Ar¹ represents phenyl, which may be substituted once or twice withfluoro, chloro, CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with fluoro, chloro, CF₃, nitroand/or cyano; or

R represents alkyl, cycloalkyl or cycloalkyl-alkyl; and

R¹ and R², independently of each another, represent hydrogen or alkyl;or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or a piperidine ring.

In a most preferred embodiment the chemical compound of the invention is

(±)-Carbamic acid tris-(4-fluorophenyl)-methyl ester;

(±)-Carbamic acid cyclohexyl-bis-(4-fluorophenyl)-methyl ester;

(±)-Carbamic acid cyclohexyl-(4-fluorophenyl)-thiazol-2-yl-methyl ester;

(±)-Piperidine-1-carboxylic acidtris-(4-fluorophenyl)-thiazol-2-yl-methyl ester;

(±)-Methyl-carbamic acid cyclopentyl-bis-(4-fluorophenyl)-methyl ester;

(±)-Pyrrolidine-1-carboxylic acid cyclohexyl-bis-(4-fluorophenyl)-methylester;

(±)-Methyl-carbamic acid tris-(4-fluorophenyl)-methyl ester;

(±)-Methyl-carbamic acidcyclohexyl-(2-fluorophenyl)-(4-fluorophenyl)-methyl ester;

(±)-Carbamic acid cyclohexyl-(4-fluorophenyl)-pyridin-2-yl-methyl ester;

(±)-Dimethyl-carbamic acid tris-(4-fluorophenyl)-methyl ester;

(±)-Carbamic acid (2-fluorophenyl)-bis-(4-fluorophenyl)-methyl ester; or

(±)-Carbamic acid (2-fluorophenyl)-(4-fluorophenyl)-phenyl-methyl ester;

an enantiomer or a mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.

In a third preferred embodiment the chemical compound of the inventionis represented by the following Formula V (Type 5)

wherein

n is 1 or 2;

m is 0, 1 or 2;

X and Y, independently of each another, represent alkyl, alkenyl,alkynyl, amino, halogen, haloalkyl, nitro and/or cyano;

Ar¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino,halogen, haloalkyl, nitro and/or cyano; and

R represents a group (Ar²) which is a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkenyl or halo-alkynyl; and

L is absent or represents alkyl; and

R¹ represents alkyl, cycloalkyl or cycloalkyl-alkyl, —CN, —C(═O)OR⁴,—C(═O)N(R⁴R⁵), —C(═S)N(R⁴R⁵), wherein R⁴ and R⁵, independently of eachanother, represent hydrogen, alkyl or phenyl, or R⁴ and R⁵, togetherwith the nitrogen atom form a heterocyclic ring selected frompyrrolidinyl and piperidinyl, or a mono- or polycyclic, carbocyclic orheterocyclic group, which carbocyclic or heterocyclic group optionallymay be substituted one or more times with alkyl, alkenyl, alkynyl,hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano.

In a more preferred embodiment

n is 1;

m is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano; or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkenyl or halo-alkynyl; and

L is absent or represents alkyl; and

R¹ represents alkyl, cycloalkyl or cycloalkyl-alkyl, —CN, —C(═O)OR⁴,—C(═O)N(R⁴R⁵), —C(═S)N(R⁴R⁵), wherein R⁴ and R⁵, independently of eachanother, represent hydrogen, alkyl or phenyl, or R⁴ and R⁵, togetherwith the nitrogen atom form a heterocyclic ring selected frompyrrolidinyl and piperidinyl, or an aromatic group selected from phenyl;2, 4 or 5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano.

In a yet more preferred embodiment

m is 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, chloro, CF₃,nitro and/or cyano;

Ar¹ represents phenyl, 2-thiazolyl, 4-thiazolyl, 2-imidazolyl,2-oxazolyl or 2-pyridinyl, which aromatic group may be substituted onceor twice with halogen, alkyl, CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with halogen, alkyl, CF₃, nitroand/or cyano; or

R represents alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl; and

L is absent or represents methylene or ethylene; and

R¹ represents alkyl, cycloalkyl or cycloalkyl-alkyl, —CN, —C(═O)OR⁴,—C(═O)N(R⁴R⁵), —C(═S)N(R⁴R⁵), wherein R⁴ and R⁵, independently of eachanother, represent hydrogen, alkyl or phenyl, or R⁴ and R⁵, togetherwith the nitrogen atom form a heterocyclic ring selected frompyrrolidinyl and piperidinyl, or an aromatic group selected from phenyl,2-thiazolyl, 4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl,which aromatic groups may be substituted once or twice with halogen,alkyl, CF₃, nitro and/or cyano.

In a most preferred embodiment the chemical compound of the invention is

2-[Cyclohexyl-(4-fluorophenyl)-(2-fluorophenyl)-methylsulfanyl]-thiazole;

2-[(2-Chlorophenyl)-cyclohexyl-(4-fluorophenyl)-(2-fluorophenyl)-methylsulfanyl]-1-methyl-1H-imidazole;

2-[(4-Chlorophenylsulfanyl)-cyclopentyl-(4-fluorophenyl)-(2-fluorophenyl)-methyl]-pyridine;

2-[Cyclohexyl-(3,4-dichlorophenyl)-(1H-imidazol-2-yl)-methylsulfanyl]-pyridine;

2-[Cyclopentyl-(2-fluorothiazol-4-yl)-(4-nitro-3-trifluoromethylphenyl)-methylsulfanyl]-pyridine;

2-[(4-fluorophenyl)-(4-fluorophenylsulfanyl)-(4-nitro-3-trifluoromethylphenyl)-methyl]-thiazole;

2-[Cyclohexylsulfanyl-(4-fluorophenyl)-(4-nitro-3-trifluoromethylphenyl)-methyl]-thiazole;

2-[Cyclopentylsulfanyl-bis-(4-fluorophenyl)-methyl]-1-methyl-1H-imidazole;

4-[Cyclohexylsulfanyl-bis-(4-fluorophenyl)-methyl]-2-fluoro-thiazole;

2-[Bis-(4-fluorophenyl)-(2-fluorophenyl)-methylsulfonyl]-thiazole;

1-Methyl-2-[tris-(4-fluorophenyl)-methylsulfanyl]-1H-imidazole;

2-[Tris-(4-fluorophenyl)-methylsulfanyl]-pyridine;

2-[Tris-(4-fluorophenyl)-methylsulfanyl]-pyridine-N-oxide;

[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-acetonitrile;

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-acetamide;

[(2-Fluoro-phenyl)-bis-(4-fluoro-phenyl)-methylsulfanyl]-acetic acid;

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-propionamide;

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-thioacetamide;

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-N,N-diethyl-acetamide;or

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-1-piperidin-1-yl-ethanone;

an enantiomer or a mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.

In a fourth preferred embodiment the chemical compound of the inventionis represented by the following Formula VI (Type 6)

wherein

m is 1 or 2;

n is 0, 1 or 2;

X and Y, independently of each another, represent alkyl, alkenyl,alkynyl, amino, halogen, haloalkyl, nitro and/or cyano;

Ar¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino,halogen, haloalkyl, nitro and/or cyano; and

R represents a group (Ar²) which is a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

L is absent or represents alkyl; and

R¹ represents cycloalkyl, or a mono- or polycyclic, carbocyclic orheterocyclic group, which carbocyclic or heterocyclic group optionallymay be substituted one or more times with alkyl, alkenyl, alkynyl,hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano.

In a more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano; or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

L is absent or represents alkyl; and

R¹ represents cycloalkyl or an aromatic group selected from phenyl,2-thiazolyl, 4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl,which aromatic groups may be substituted once or twice with halogen,alkyl, CF₃, nitro and/or cyano.

In a yet more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, chloro, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with halogen, alkyl, CF₃, nitroand/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with halogen, alkyl, CF₃, nitroand/or cyano; or

R represents alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl, halo-alkyl;and

L is absent or represents methylene or ethylene; and

R¹ represents cycloalkyl or an aromatic group selected from phenyl,2-thiazolyl, 4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl,which aromatic groups may be substituted once or twice with halogen,methyl, CF₃, nitro and/or cyano.

In a still more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl and 2-thiazolyl,which aromatic groups may be substituted once or twice with fluoro, CF₃,nitro and/or cyano;

Ar² represents phenyl, which may be substituted once or twice withfluoro, CF₃, nitro and/or cyano; or

R represents cycloalkyl or cycloalkyl-alkyl; and

L is absent or represents —CH₂—; and

R¹ represents cycloalkyl, phenyl, 2-thiazolyl, 2-imidazolyl or2-pyridinyl, which aromatic groups may be substituted once with fluoro,CF₃, nitro and/or cyano; or

R¹ represents 2-thiazolyl-methyl.

In a most preferred embodiment the chemical compound of the invention is

Methyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-1);

Ethyl (bis(4-fluorophenyl)phenyl)methyl sulfoxide (Compound 6-2);

Cyclohexylmethyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-3);

Cyclohexyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-4);

Isopropyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-5);

(2-Thiazolyl)methyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-6);

Phenyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-7);

1-Methyl-2-imidazolyl tris(4-fluorophenyl)methyl) sulfoxide (Compound6-8);

2-Pyridyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-9);

(Cyclohexyl-bis(4-fluorophenyl))methyl phenyl sulfoxide (Compound 6-10);

(Cyclopentyl-bis(4-fluorophenyl))methyl methyl sulfoxide (Compound6-11); or

(Cyclohexyl-(4-fluorophenyl)-(2-thiazolyl))methyl methyl sulfoxide(Compound 6-12);

an enantiomer or a mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.

In a fifth preferred embodiment the chemical compound of the inventionis represented by the following Formula VII (Type 7)

wherein

m is 1 or 2;

n is 0, 1 or 2;

X and Y, independently of each another, represent alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;

Ar¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino,halogen, haloalkyl, nitro and/or cyano; and

R represents a group (Ar²) which is a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

L may be absent or represents alkyl; and

R¹ represents alkyl, cycloalkyl or a mono- or polycyclic, carbocyclic orheterocyclic group, which carbocyclic or heterocyclic group optionallymay be substituted one or more times with alkyl, alkenyl, alkynyl,hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano.

In a more preferred embodiment

m is 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano; or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

L may be absent or represents alkyl; and

R¹ represents alkyl, cycloalkyl or an aromatic group selected fromphenyl; 2, 4 or 5-thiazolyl; isothiazolyl, in particular 3, 4 or5-isothiazolyl; imidazolyl, in particular 1, 2 or 4-imidazolyl;oxazolyl, in particular 2, 4 or 5-oxazolyl; isoxazolyl, in particular 3,4 or 5-isoxazolyl; pyridinyl, in particular 2, 3 or 4-pyridinyl;pyrimidinyl, in particular 2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl),in particular 1, 2 or 3-pyrrolyl; which aromatic group may besubstituted once or twice with alkyl, alkenyl, alkynyl, hydroxy, alkoxy,amino, halogen, haloalkyl, nitro and/or cyano.

In a yet more preferred embodiment

m is 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, chloro, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with fluoro, chloro, methyl,CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with fluoro, chloro, methyl,CF₃, nitro and/or cyano; or

R represents alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl, halo-alkyl;and

L may be absent or represents methylene or ethylene; and

R¹ represents alkyl, cycloalkyl or an aromatic group selected fromphenyl, 2-thiazolyl, 4-thiazolyl, 2-imidazolyl, 2-oxazolyl and2-pyridinyl, which aromatic groups may be substituted once or twice withfluoro, chloro, methyl, CF₃, nitro and/or cyano.

In a still more preferred embodiment

m is 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, chloro, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl and 2-thiazolyl,which aromatic groups may be substituted once or twice with fluoro,chloro, methyl, CF₃, nitro and/or cyano;

Ar² represents phenyl, which may be substituted once or twice withfluoro, CF₃, nitro and/or cyano; or

R represents alkyl, cycloalkyl or cycloalkyl-alkyl; and

L may be absent or represents methylene; and

R¹ represents alkyl or cycloalkyl; or

R¹ represents phenyl, 2-thiazolyl, 2-imidazolyl or 2-pyridinyl, whicharomatic groups may be substituted once or twice with fluoro, chloro,methyl, CF₃, nitro and/or cyano.

In a most preferred embodiment the chemical compound of the invention is

Methyl tris(4-fluorophenyl)methyl sulfone (Compound 7-1);

Ethyl (bis(4-fluorophenyl)phenyl)methyl sulfone (Compound 7-2);

Cyclohexylmethyl tris(4-fluorophenyl)methyl sulfone (Compound 7-3);

Cyclohexyl tris(4-fluorophenyl)methyl sulfone (Compound 7-4);

Isopropyl tris(4-fluorophenyl)methyl sulfone (Compound 7-5);

(2-Thiazolyl)methyl tris(4-fluorophenyl)methyl sulfone (Compound 7-6);

Phenyl tris(4-fluorophenyl)methyl sulfone (Compound 7-7);

1-Methyl-2-imidazolyl tris(4-fluorophenyl)methyl) sulfone (Compound7-8);

2-Pyridyl tris(4-fluorophenyl)methyl sulfone (Compound 7-9);

(Cyclohexyl-bis(4-fluorophenyl))methyl phenyl sulfone (Compound 7-10);

(Cyclopentyl-bis(4-fluorophenyl))methyl methyl sulfone (Compound 7-11);

(Cyclohexyl-(4-fluorophenyl)-(2-thiazolyl))methyl methyl sulfone(Compound 7-12);

((2-Fluorophenyl)-bis(4-fluorophenyl)-phenyl)methyl methyl sulfone(Compound 7-13); or

Methanesulphonyl-2-fluorophenyl-bis-(4-fluoro-phenyl) methane;

an enantiomer or a mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.

In a sixth preferred embodiment the chemical compound of the inventionis represented by Formula VIII (Type 8)

wherein

m is 0, 1 or 2;

n is 0, 1 or 2;

X and Y, independently of each another, represent alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;

Ar¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino,halogen, haloalkyl, nitro and/or cyano; and

R represents a group (Ar²) which is a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl and/or a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupsoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R¹ and R², together with the N atom to which they are bound, form a 5-to 7-membered heterocyclic ring.

In a more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano; or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl or cycloalkyl-alkyl, or an aromatic group selected fromphenyl; 2, 4 or 5-thiazolyl; isothiazolyl, in particular 3, 4 or5-isothiazolyl; imidazolyl, in particular 1, 2 or 4-imidazolyl;oxazolyl, in particular 2, 4 or 5-oxazolyl; isoxazolyl, in particular 3,4 or 5-isoxazolyl; pyridinyl, in particular 2, 3 or 4-pyridinyl;pyrimidinyl, in particular 2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl),in particular 1, 2 or 3-pyrrolyl; which aromatic group may besubstituted once or twice with alkyl, alkenyl, alkynyl, hydroxy, alkoxy,amino, halogen, haloalkyl, nitro and/or cyano; or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or piperidine ring.

In a yet more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents phenyl, 2-thiazolyl, 4-thiazolyl, 2-imidazolyl,2-oxazolyl and 2-pyridinyl, which aromatic groups may be substitutedonce or twice with halogen, alkyl, CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with halogen, alkyl, CF₃, nitroand/or cyano; or

R represents alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl or halo-alkyl;and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl or cycloalkyl-alkyl, or an aromatic group selected fromphenyl, 2-thiazolyl, 4-thiazolyl, 2-imidazolyl, 2-oxazolyl and2-pyridinyl, which aromatic groups may be substituted once or twice withhalogen, alkyl, CF₃, nitro and/or cyano; or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or piperidine ring.

In a still more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, CF₃, nitroand/or cyano;

Ar¹ represents phenyl, 2-thiazolyl, 4-thiazolyl, 2-imidazolyl,2-oxazolyl and 2-pyridinyl, which aromatic groups may be substitutedonce or twice with fluoro, chloro, methyl, CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with fluoro, chloro, methyl,CF₃, nitro and/or cyano; or

R represents alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl or halo-alkyl;and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl or cycloalkyl-alkyl, or 2-oxazolyl, which may be substitutedwith fluoro, methyl, CF₃, nitro or cyano; or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or piperidine ring.

In a most preferred embodiment the chemical compound of the invention is

Tris-(4-fluorophenyl)-methanesulfinic acid amide;

Bis-(4-fluorophenyl)-phenyl-methanesulfinic acid methylamide;

Tris-(4-fluorophenyl)-methanesulfinic acid cyclohexylamide;

1-[Tris-(4-fluorophenyl)-methanesulfinyl]-piperidine;

Tris-(4-fluorophenyl)-methanesulfinic acid dimethylamide;

Tris-(4-fluorophenyl)-methanesulfinic acid thiazol-2-ylamide;

Tris-(4-fluorophenyl )-methanesulfinic acid (4-fluorophenyl)-amide;

Bis-(4-fluorophenyl)-(1-methyl-1H-imidazol-2-yl)-methanesulfinic acidmethylamide;

Cyclohexyl-(4-fluorophenyl)-thiazol-2-yl-methanesulfinic acid amide;

Bis-(4-fluorophenyl)-(1-methyl-1H-imidazol-2-yl)-methanesulfinic acidamide;

Bis-(4-fluorophenyl)-thiazol-2-yl-methanesulfinic acid amide; or

Bis-(4-fluorophenyl)-oxazol-2-yl-methanesulfinic acid amide;

an enantiomer or a mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.

In a seventh preferred embodiment the chemical compound of the inventionis represented by Formula IX (Type 9)

wherein

m is 0, 1 or 2;

n is 0, 1 or 2;

X and Y, independently of each another, represent alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;

Ar¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino,halogen, haloalkyl, nitro and/or cyano; and

R represents a group (Ar²) which is a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl and/or a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupsoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R¹ and R², together with the N atom to which they are bound, form a 5-to 7-membered heterocyclic ring.

In a more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano; or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl and/or an aromatic group selected fromphenyl; 2, 4 or 5-thiazolyl; isothiazolyl, in particular 3, 4 or5-isothiazolyl; imidazolyl, in particular 1, 2 or 4-imidazolyl;oxazolyl, in particular 2, 4 or 5-oxazolyl; isoxazolyl, in particular 3,4 or 5-isoxazolyl; pyridinyl, in particular 2, 3 or 4-pyridinyl;pyrimidinyl, in particular 2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl),in particular 1, 2 or 3-pyrrolyl; which aromatic group may besubstituted once or twice with alkyl, alkenyl, alkynyl, hydroxy, alkoxy,amino, halogen, haloalkyl, nitro and/or cyano; or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or a piperidine ring.

In a yet more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, chloro, CF₃,nitro and/or cyano;

Ar¹ represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with halogen, alkyl, CF₃, nitroand/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with halogen, alkyl, CF₃, nitroand/or cyano; or

R represents alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl or halo-alkyl;and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl and/or an aromatic group selected fromphenyl, 2-thiazolyl, 4-thiazolyl, 2-imidazolyl, 2-oxazolyl and2-pyridinyl, which aromatic groups may be substituted once or twice withhalogen, alkyl, CF₃, nitro and/or cyano; or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or a piperidine ring.

In a still more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, CF₃, nitroand/or cyano;

Ar¹ represents phenyl or 2-thiazolyl, which may be substituted once withfluoro, chloro, methyl, CF₃, nitro or cyano;

Ar² represents phenyl, which may be substituted once with fluoro, CF₃,nitro or cyano; or

R represents cycloalkyl or cycloalkyl-alkyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl and/or an aromatic group selected fromphenyl, 2-thiazolyl, 4-thiazolyl, 2-imidazolyl, 2-oxazolyl; or

R¹ and R², together with the N atom to which they are bound, form apyrrolidine or a piperidine ring.

In a most preferred embodiment the chemical compound of the invention is

Thiocarbamic acid S-[tris-(4-fluorophenyl)-methyl] ester;

Thiocarbamic acid S-[cyclohexyl-bis-(4-fluorophenyl)-methyl] ester;

Thiocarbamic acid S-[cyclohexyl-(4-fluorophenyl)-thiazol-2-yl-methyl]ester;

Piperidine-1-carbothioic acid S-[tris-(4-fluorophenyl)-methyl] ester;

Methyl-thiocarbamic acid S-[cyclopentyl-bis-(4-fluorophenyl)-methyl]ester;

Pyrrolidine-1-carbothioic acidS-[cyclohexyl-bis-(4-fluorophenyl)-methyl] ester;

Methyl-thiocarbamic acid S-[tris-(4-fluorophenyl)-methyl] ester;

Methyl-thiocarbamic acidS-[cyclopentyl-(2-fluorophenyl)-(4-fluorophenyl)-methyl] ester;

Thiocarbamic acid S-[cyclohexyl-(4-fluorophenyl)-pyridin-2-yl-methyl]ester;

Dimethyl-thiocarbamic acid S-[tris-(4-fluorophenyl)-methyl] ester;

Thiocarbamic acid S-[(2-fluorophenyl)-bis-(4-fluorophenyl)-methyl]ester; or

Thiocarbamic acid S-[(2-fluorophenyl)-(4-fluorophenyl)-phenyl-methyl]ester;

an enantiomer or a mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.

In an eight preferred embodiment the chemical compound of the inventionis represented by Formula X (Type 10)

wherein

m is 1 or 2;

n is 0, 1 or 2;

X and Y, independently of each another, represent alkyl, alkenyl,alkynyl, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;

Ar¹ represents a phenyl group substituted one or more times with alkyl,alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitroand/or cyano; and

R represents a group (Ar²) which is a mono- or polycyclic, heterocyclicgroup other than imidazolyl, which carbocyclic or heterocyclic group mayoptionally be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl,cycloalkyl or cycloalkyl-alkyl; or

R¹ and R² together with the phosphor and the oxygen atoms to which theyare bound form a 5- to 7-membered heterocyclic ring.

In a more preferred embodiment

m is 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, alkyl, CF₃,nitro and/or cyano;

Ar¹ represents a phenyl group substituted once or twice with halogen,alkyl, CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;oxazolyl, in particular 2, 4 or 5-oxazolyl; isoxazolyl, in particular 3,4 or 5-isoxazolyl; pyridinyl, in particular 2, 3 or 4-pyridinyl;pyrimidinyl, in particular 2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl),in particular 1, 2 or 3-pyrrolyl; which aromatic group may besubstituted once or twice with alkyl, alkenyl, alkynyl, hydroxy, alkoxy,amino, halogen, haloalkyl, nitro and/or cyano; or

R represents alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl or halo-alkyl;and

R¹ and R², independently of each another, represent alkyl, cycloalkyl orcycloalkyl-alkyl; or

R¹ and R² together with the phosphor and the oxygen atoms to which theyare bound form a 5-to 6-membered heterocyclic ring.

In a yet more preferred embodiment

m is 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, chloro, CF₃,nitro 5 and/or cyano;

Ar¹ represents phenyl, substituted once or twice with fluoro, chloro,CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-oxazolyl and 2-pyridinyl, which aromatic group optionallymay be substituted once or twice with fluoro, chloro, methyl, CF₃, nitroand/or cyano; or

R represents alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl or halo-alkyl;and

R¹ and R², independently of each another, represent alkyl, cycloalkyl orcycloalkyl-alkyl; or

R¹ and R² together with the phosphor and the oxygen atoms to which theyare bound form a 5-membered heterocyclic dioxaphospholane ring.

In a still more preferred embodiment

m is 1;

n is 0 or 1;

X and Y, independently of each another, represent fluoro, CF₃, nitroand/or cyano;

Ar¹ represents phenyl, which is substituted once or twice with fluoro,CF₃, nitro and/or cyano;

Ar² represents phenyl or 2-thiazolyl, which aromatic group mayoptionally be substituted once or twice with fluoro, methyl, CF₃, nitroand/or cyano; or

R represents alkyl, cycloalkyl or cycloalkyl-alkyl; and

R¹ and R², independently of each another, represent alkyl or cycloalkyl;or

R¹ and R² together with the phosphor and the oxygen atoms to which theyare bound form a 5-membered heterocyclic dioxaphospholane ring.

In a most preferred embodiment the chemical compound of the invention is

[Cyclohexyl-bis-(4-fluorophenyl)-methyl]-phosphonic acid dimethyl ester;

[Cyclopentyl-bis-(4-fluorophenyl)-methyl]-phosphonic acid dipropylester;

[1,1-Bis-(4-fluorophenyl)-hexyl]-phosphonic acid dimethyl ester;

[1,1-Bis-(4-fluorophenyl)-2-methyl-propyl]-phosphonic acid dimethylester;

[Bis-(4-fluorophenyl)-pyridin-2-yl-methyl]-phosphonic acid dimethylester;

[Bis-(4-fluorophenyl)-thiazol-2-yl-methyl]-phosphonic acid dimethylester;

[Tris-(4-fluoro-phenyl)-methyl]-phosphonic acid dimethyl ester;

[(2-Fluoro-phenyl)-bis-(4-fluoro-phenyl)-methyl]-phosphonic aciddimethyl ester;

[(2-Chloro-phenyl)-(2-fluoro-phenyl)-(4-fluoro-phenyl)-methyl]-phosphonicacid dimethyl ester;

[(4-Chloro-phenyl)-bis-(4-fluoro-phenyl)-methyl]-phosphonic aciddimethyl ester;

[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methyl]-phosphonic acid; or

[Bis-(4-fluoro-phenyl)-p-tolyl-methyl]-phosphonic acid;

an enantiomers or a mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.

In a ninth preferred embodiment the chemical compound of the inventionis represented by Formula XII (Type 12)

wherein

m is 0, 1 or 2;

n is 0, 1 or 2;

X and Y, independently of each another, represent alkenyl, alkynyl,alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;

Ar¹ represents a mono- or polycyclic, carbocyclic or heterocyclic group,which carbocyclic or heterocyclic group optionally may be substitutedone or more times with alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino,halogen, haloalkyl, nitro and/or cyano; and

R represents a group (Ar²) which is a mono- or polycyclic, carbocyclicor heterocyclic group, which carbocyclic or heterocyclic groupoptionally may be substituted one or more times with alkyl, alkenyl,alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl, nitro and/or cyano;or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl oralkoxy; or

R¹ and R² together with the phosphor and the oxygen atoms to which theyare bound form a heterocyclic (dioxaphospholane) ring.

In a more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, CF₃, nitroand/or cyano;

Ar¹ represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl; 2, 4 or5-thiazolyl; isothiazolyl, in particular 3, 4 or 5-isothiazolyl;imidazolyl, in particular 1, 2 or 4-imidazolyl; oxazolyl, in particular2, 4 or 5-oxazolyl; isoxazolyl, in particular 3, 4 or 5-isoxazolyl;pyridinyl, in particular 2, 3 or 4-pyridinyl; pyrimidinyl, in particular2, 4 or 5-pyrimidinyl; and pyrrolyl (azolyl), in particular 1, 2 or3-pyrrolyl; which aromatic group may be substituted once or twice withalkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, halogen, haloalkyl,nitro and/or cyano; or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl oralkoxy; or

R¹ and R² together with the phosphor and the oxygen atoms to which theyare bound form a heterocyclic (dioxaphospholane) ring.

In a yet more preferred embodiment

m is 0 or 1;

n is 0 or 1;

X and Y, independently of each another, represent halogen, CF₃, nitroand/or cyano;

Ar¹ represents phenyl, which may be substituted once or twice withhalogen, alkyl, CF₃, nitro and/or cyano;

Ar² represents an aromatic group selected from phenyl, 2-thiazolyl,4-thiazolyl, 2-imidazolyl, 2-oxazolyl and 2-pyridinyl, which aromaticgroups may be substituted once or twice with halogen, alkyl, CF₃, nitroand/or cyano; or

R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,halo-alkyl, halo-alkenyl or halo-alkynyl; and

R¹ and R², independently of each another, represent hydrogen, alkyl oralkoxy; or

R¹ and R² together with the phosphor and the oxygen atoms to which theyare bound form a heterocyclic (dioxaphospholane) ring.

In a most preferred embodiment the chemical compound of the invention is

[Bis-(4-fluorophenyl)-isopropoxy-methyl]-phosphonic acid dimethyl ester;

[(2-Fluorophenyl)-(4-fluorophenyl)-isobutoxy-methyl]-phosphonic aciddimethyl ester;

[(3-Fluorophenyl)-(4-fluorophenyl)-(4-nitro-3-trifluoromethyl-phenoxy)-methyl]-phosphonicacid dimethyl ester;

2-[Bis-(4-fluorophenyl)-isopropoxy-methyl]-[1,3,2]-dioxaphospholane2-oxide;

[Cyclohexyl-(4-nitro-3-trifluoromethyl-phenyl)-(pyridin-2-yloxy)-methyl]-phosphonicacid dimethyl ester;

[Cyclohexyl-(4-fluorophenyl)-(4-nitro-3-trifluoromethyl-phenoxy)-methyl]-phosphonicacid dipropyl ester;

[(4-Chlorophenyl)-(4-fluorophenyl)-(4-nitro-3-trifluoromethyl-phenoxy)-methyl]-phosphonicacid dimethyl ester;

[1-(3,4-Dichlorophenoxy)-1-(4-fluorophenyl)-hexyl]-phosphonic aciddimethyl ester;

[1-(4-Fluorophenyl)-2-methyl-1-(4-nitro-3-trifluoromethyl-phenoxy)-propyl]-phosphonicacid dimethyl ester;

[(4-Fluorophenyl)-(6-fluoropyridin-2-yloxy)-(4-nitro-3-trifluoromethyl-phenyl)-methyl]-phosphonicacid dimethyl ester;

[(3,4-Dichlorophenyl)-(6-fluoropyridin-3-yloxy)-thiazol-2-yl-methyl]-phosphonicacid dimethyl ester; or

[(4-Fluorophenyl)-(1-methyl-1H-imidazol-2-yl)-(4-nitro-3-trifluoromethyl-phenoxy)-methyl]-phosphonicacid dimethyl ester;

an enantiomer or a mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.

Any possible combination of two or more of the embodiments describedherein is comprised within the scope of the present invention.

Definition of Substituents

In the context of this invention halogen represents a fluorine, achlorine, a bromine or an iodine atom.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to eighteen carbon atoms (C₁₋₁₈-alkyl),more preferred of from one to six carbon atoms (C₁₋₆-alkyl; loweralkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyland isohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkylgroup, including butyl, isobutyl, secondary butyl, and tertiary butyl.In another preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention a haloalkyl group designates an alkylgroup as defined herein, which alkyl group is substituted one or moretimes with halogen. Preferred haloalkyl groups of the invention includetrihalogenmethyl.

In the context of this invention a hydroxy-alkyl group designates analkyl group substituted with OH, wherein alkyl is as defined above.

In the context of this invention a cyano-alkyl group designates an alkylgroup substituted with CN, wherein alkyl is as defined above.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to eight carbon atoms (C₂₋₈-alkenyl),more preferred of from two to six carbon atoms (C₂₋₆-alkenyl), includingat least one double bond. In a most preferred embodiment the alkenylgroup of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or3-butenyl, 1,3-butdienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1,3-hexdienyl,or 1,3,5-hextrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl,1,3-octdienyl, 1,3,5-octtrienyl, or 1,3,5,7-octtetraenyl.

In the context of this invention a haloalkenyl group designates analkenyl group as defined herein, which alkenyl group is substituted oneor more times with halogen.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to eight carbon atoms (C₂₋₈-alkynyl),more preferred of rom two to six carbon atoms (C₂₋₆-alkynyl), includingat least one triple bond. In its most preferred embodiment the alkynylgroup of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or3-butynyl, 1,3-butdiynyl; 1-, 2-, 3-, 4-pentynyl, 1,3-pentdiynyl; 1-,2-, 3-, 4-, or 5-henynyl, 1,3-hexdiynyl, 1,3,5-hextriynyl; 1-, 2-, 3-,4-, 5- or 6-heptynyl, 1,3-heptdiynyl, 1,3,5-hepttriynyl; 1-, 2-, 3-, 4-,5-, 6- or 7-octynyl, 1,3-octdiynyl, 1,3,5-octtriynyl, or1,3,5,7-octtetraynyl.

In the context of this invention a haloalkynyl group designates analkynyl group as defined herein, which alkynyl group is substituted oneor more times with halogen.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

In the context of this invention a cycloalkyl-alkyl group designates acycloalkyl group as defined above, which cycloalkyl group is substitutedon an alkyl group as also defined above. Examples of preferredcycloalkyl-alkyl groups of the invention include cyclopropylmethyl andcyclopropylethyl.

In the context of this invention an alkoxy group designates an“alkyl-O—” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy groups of the invention include methoxy and ethoxy.

In the context of this invention an alkoxy-alkyl group designates an“alkyl-O-alkyl-” group, and an alkoxy-alkoxy-alkyl group designates an“alkyl-O-alkyl-O-alkyl-” group, wherein alkyl is as defined above.Examples of preferred alkoxy-alkyl groups of the invention includemethoxy-methyl, methoxy-ethyl, ethoxy-methyl, and ethoxy-ethyl, andexamples of preferred alkoxy-alkoxy-alkyl groups of the inventioninclude methoxy-methoxy-methyl, methoxy-methoxy-ethyl,methoxy-ethoxy-methyl, and methoxy-ethoxy-ethyl.

In the context of this invention an alkoxy-alkoxy group designates an“alkyl-O-alkyl-O—” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy-alkoxy groups of the invention include methoxy-methoxy,methoxy-ethoxy, ethoxy-methoxy, and ethoxy-ethoxy.

In the context of this invention an alkoxy-alkoxy-akyl group designatesan “alkyl-O-alkyl-O-alkyl-” group, wherein alkyl is as defined above.Examples of preferred alkoxy-alkoxy groups of the invention includemethoxy-methoxy-methyl, methoxy-ethoxy-methyl, ethoxy-methoxy-methyl,ethoxy-ethoxy-methyl, methoxy-methoxy-ethyl, methoxy-ethoxy-ethyl,ethoxy-methoxy-ethyl, and ethoxy-ethoxy-ethyl.

In the context of this invention an acyl group designates a carboxygroup (—COOH) or an alkyl-carbonyl group (alkyl-CO—), wherein alkyl isas defined above. Examples of preferred acyl groups of the inventioninclude carboxy, acetyl, and propionyl.

In the context of this invention an alkoxy-carbonyl group designates an“alkyl-O—CO—” group, and an alkoxy-alkoxy-carbonyl group designates an“alkyl-O-alkyl-O—CO—” group, wherein alkyl is as defined above.

In the context of this invention an amino group may be a primary (—NH₂),secondary (—NH-alkyl), or tertiary (—N(alkyl)₂) amino group, i.e. it maybe substituted once or twice with an alkyl group as defined above.

In the context of this invention a mono-, bi- or polycyclic carbocyclicgroup is a mono-, bi- or polycyclic compound, which holds only carbonatoms in its ring structure. The ring structures may in particular bearomatic (i.e. aryl) or partially or fully saturated.

In the context of this invention an aryl group designates a monocyclicor polycyclic aromatic hydrocarbon group. Examples of preferred arylgroups of the invention include phenyl, indenyl, naphthyl, azulenyl,fluorenyl, and anthracenyl.

In the context of this invention an aralkyl group designates an arylgroup as defined above, which aryl group is attached to an alkyl groupas also defined above. Examples of preferred aralkyl groups of theinvention include benzyl.

In the context of this invention a mono-, bi- or polycyclic heterocyclicgroup is a mono-, bi- or polycyclic compound, which holds one or moreheteroatoms in its ring structure. Preferred heteroatoms includenitrogen (N), oxygen (O), and sulphur (S). One or more of the ringstructures may in particular be aromatic or partially saturated (i.e. aheteroaryl), or fully saturated.

Preferred monocyclic heteroaryl groups of the invention include aromatic5- and 6 membered heterocyclic monocyclic groups, including furanyl, inparticular 2- or 3-furanyl; thienyl, in particular 2 or 3-thienyl;pyrrolyl (azolyl), in particular 1,2 or 3-pyrrolyl; oxazolyl, inparticular oxazol-2,4 or 5-yl; thiazolyl, in particular thiazol-2,4 or5-yl; imidazolyl, in particular 1,2 or 4-imidazolyl; pyrazolyl, inparticular 1,3 or 4-pyrazolyl; isoxazolyl, in particular isoxazol-3,4 or5-yl; isothiazolyl, in particular isothiazol-3,4 or 5-yl; oxadiazolyl,in particular 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazol-3,4 or 5-yl;triazolyl, in particular 1,2,3-, 1,2,4-, 2,1,3- or 4,1,2-triazolyl;thiadiazolyl, in particular thiadiazol-3,4 or 5-yl; pyridinyl, inparticular 2,3 or 4-pyridinyl; pyridazinyl, in particular 3 or4-pyridazinyl; pyrimidinyl, in particular 2,4 or 5-pyrimidinyl;pyrazinyl, in particular 2 or 3-pyrazinyl; and triazinyl, in particular1,2,3-, 1,2,4- or 1,3,5-triazinyl.

Preferred bicyclic heteroaryl groups of the invention includeindolizinyl, in particular 2,5 or 6-indolizinyl; indolyl, in particular2,5 or 6-indolyl; isoindolyl, in particular 2,5 or 6-isoindolyl;benzo[b]furanyl, in particular 2,5 or 6-benzofuranyl; benzo[b]thienyl,in particular 2,5 or 6-benzothienyl; benzimidazolyl, in particular 2,5or 6-benzimidazolyl; benzothiazolyl, in particular 5 or6-benzothiazolyl; purinyl, in particular 2 or 8-purinyl; quinolinyl, inparticular 2,3,6 or 7-quinolinyl; isoquinolinyl, in particular 3,6 or7-isoquinolinyl; cinnolinyl, in particular 6 or 7-cinnolinyl;phthalazinyl, in particular 6 or 7-phthalazinyl; quinazolinyl, inparticular 2,6 or 7-quinazolinyl; quinoxalinyl, in particular 2 or6-quinoxalinyl; 1,8-naphthyridinyl, in particular 1,8-naphthyridin-2,3,6or 7-yl; pteridinyl, in particular 2,6 or 7-pteridinyl; and indenyl, inparticular 1,2,3,5 or 5-indenyl.

In the context of this invention a heteroaryl-alkyl group designates amono-, bi- or poly-heterocyclic group as described above, whichheterocyclic group is attached to an alkyl group as also defined above.Examples of preferred hetero-alkyl groups of the invention includefurfuryl and picolyl.

In the context of this invention an N-oxide designates an oxidederivative of a nitrogen containing compound, e.g. N-containingheterocyclic compounds capable of forming such N-oxides.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate derived, the phthalate,the salicylate, the sorbate, the stearate, the succinate, the tartrate,the toluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Metal salts of a chemical compound of the invention include alkali metalsalts such as the sodium salt of a chemical compound of the inventioncontaining a carboxy group.

Steric Isomers

The chemical compounds of the invention may exist in (+) and (−) formsas well as in racemic forms (±). The racemates of these isomers and theindividual isomers themselves are within the scope of the presentinvention.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or I- (tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Methods of Preparation

The chemical compounds of the invention may be prepared by conventionalmethods for chemical synthesis, e.g. those described in the workingexamples. The starting materials for the processes described in thepresent application are known or may readily be prepared by conventionalmethods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

According to the present invention it has now been found that thechemical compounds of the invention possess valuable activity asmodulators of SK_(Ca) and/or IK_(Ca) channels, in particular by havingan inhibitory activity.

The SK/IK/BK channel modulating or inhibiting activity may be monitoredusing conventional electrophysiological methods such as patch-clamptechniques, or conventional spectroscopic methods such as FLIPR assay(Fluorescence Image Plate Reader; available from Molecular Devices).These methods generally comprises subjecting an SK_(Ca) and/or IK_(Ca)containing cell to the action of the chemical compound of the invention,followed by monitoring the membrane potential of the SK_(Ca) and/orIK_(Ca) containing cell in order to identify changes in the membranepotential caused by the action of the compound of the invention. Usingsuch methods the chemical compounds of the invention show IK_(Ca)inhibitory activity in concentrations below 100 μM, preferably below 10μM, more preferred below 1 μm. In its most preferred embodimentcompounds show IK_(Ca) inhibitory activity show activity in lowmicromolar and the nanomolar range.

Based on their biological activity the compounds of the invention areconsidered useful for the for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to modulationof SK_(Ca) and/or IK_(Ca) channels, including diseases or conditionslike respiratory diseases such as asthma, cystic fibrosis, chronicobstructive pulmonary disease and rhinorrhea, convulsions, vascularspasms, coronary artery spasms, renal disorders, polycystic kidneydisease, bladder spasms, urinary incontinence, bladder outflowobstruction, irritable bowel syndrome, gastrointestinal dysfunction,secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearthdisease, angina pectoris, coronary hearth disease, traumatic braininjury, psychosis, anxiety, depression, dementia, memory and attentiondeficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud'sdisease, intermittent claudication, Sjorgren's syndrome, migraine,arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia,xerostomi, diabetes type II, hyperinsulinemia, premature labour,baldness, cancer, and immune suppression.

The compounds of the invention are considered particularly useful forreducing or inhibiting undesired immune-regulatory actions. In apreferred embodiment, therefore, the compounds of the may be used in thetreatment or alleviation of a diseases, disorders or condition relatedto immune dysfunction, or in order to obtain immune suppression in anindividual in need therefore.

In a more preferred embodiment, the invention relates to the use of anIK_(Ca) inhibitory compound of the invention in a combination therapywith known immune-suppressants for the treatment or alleviation of adiseases, disorders or condition related to immune dysfunction, or forobtaining immune suppression. Preferred immune-suppressants to combinewith the compounds of the invention include Amphotericin, Busulphan,Co-trimoxazole, Chlorambucil, colony stimulating factors,corticosteroids, Cyclophosphamide, Fluconazole, folinic acid,Ganciclovir, antilymphocyte immunoglobulins, normal immunoglobulins,Methotrexate, Methylprednisolone, Octreotide, Oxpentifylline, Tacrolimus(FK506), Thalidomide, Zolimomab aritox, and the calcineurin inhibitors(protein phosphatase 2B inhibitors), in particular Cyclosporin.

Conditions which may benefit from this treatment include, but are notlimited to diseases, disorders or conditions such as auto-immunediseases, e.g. Addison's disease, alopecia areata, Ankylosingspondylitis, haemolytic anemia (anemia haemolytica), pernicious anemia(anemia perniciosa), aphthae, aphthous stomatitis, arthritis,arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis,aspermiogenese, asthma bronchiale, auto-immune asthma, auto-immunehemolysis, Bechet's disease, Boeck's disease, inflammatory boweldisease, Burkitt's lymphoma, Chron's disease, chorioiditis, colitisulcerosa, Coeliac disease, cryoglobulinemia, dermatitis herpetiformis,dermatomyositis, insulin-dependent type I diabetes, juvenile diabetes,idiopathic diabetes insipidus, insulin-dependent diabetes mellisis,auto-immune demyelinating diseases, Dupuytren's contracture,encephalomyelitis, encephalomyelitis allergica, endophthalmiaphacoanaphylactica, enteritis allergica, auto-immune enteropathysyndrome, erythema nodosum leprosum, idiopathic facial paralysis,chronic fatigue syndrome, febris rheumatica, glomerulo nephritis,Goodpasture's syndrome, Graves' disease, Hamman-Rich's disease,Hashimoto's disease, Hashimoto's thyroiditis, sudden hearing loss,sensoneural hearing loss, hepatitis chronica, Hodgkin's disease,haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, iritis,leucopenia, leucemia, lupus erythematosus disseminatus, systemic lupuserythematosus, cutaneous lupus erythematosus, lymphogranuloma malignum,mononucleosis infectiosa, myasthenia gravis, traverse myelitis, primaryidiopathic myxedema, nephrosis, ophthalmia symphatica, orchitisgranulomatosa, pancreatitis, pemphigus, pemphigus vulgaris,polyarteritis nodosa, polyarthritis chronica primaria, polymyositis,polyradiculitis acuta, psoreasis, purpura, pyoderma gangrenosum,Quervain's thyreoiditis, Reiter's syndrome, sarcoidosis, ataxicsclerosis, progressive systemic sclerosis, scleritis, sclerodermia,multiple sclerosis, sclerosis disseminata, acquired spenic atrophy,infertility due to antispermatozoan antobodies, thrombocytopenia,idiopathic thrombocytopenia purpura, thymoma, acute anterior uveitis,vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated diseasessuch as Sjorgren's syndrome, virus (AIDS or EBV) associated B celllymphoma, parasitic diseases such as Lesihmania, and immunosuppresseddisease states such as viral infections following allografttransplantations, graft vs. Host syndrome, transplant rejection, orAIDS, cancers, chronic active hepatitis diabetes, toxic chock syndrome,food poisoning, and transplant rejection.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefore, and,optionally, other therapeutic and/or prophylactic ingredients, know andused in the art. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notharmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered byany convenient route, which suits the desired therapy. Preferred routesof administration include oral administration, in particular in tablet,in capsule, in dragé, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition of the inventioncan be manufactured by any skilled person by use of standard methods andconventional techniques appropriate to the desired formulation. Whendesired, compositions adapted to give sustained release of the activeingredient may be employed.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to inhibition of SK_(Ca) and/or IK_(Ca)channels, and which method comprises administering to such a livinganimal body, including a human, in need thereof an effective amount of achemical compound of the invention.

In a more preferred embodiment the disease or a disorder or a conditionis a respiratory diseases such as asthma, cystic fibrosis, chronicobstructive pulmonary disease and rhinorrhea, convulsions, vascularspasms, coronary artery spasms, renal disorders, polycystic kidneydisease, bladder spasms, urinary incontinence, bladder outflowobstruction, irritable bowel syndrome, gastrointestinal dysfunction,secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearthdisease, angina pectoris, coronary hearth disease, traumatic braininjury, psychosis, anxiety, depression, dementia, memory and attentiondeficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud'sdisease, intermittent claudication, Sjorgren's syndrome, migraine,arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia,xerostomi, diabetes type II, hyperinsulinemia, premature labour,baldness, cancer, and immune suppression.

In an even more preferred embodiment, the disease, disorder or conditionrelates to reduction or inhibition of undesired immune-regulatoryactions, including graft vs. host syndrome, transplant rejection, ortransplant rejection. In a further preferred embodiment this methodcomprises simultaneous administration of a pharmaceutically effectiveamount of a conventional immune suppressing agent. Conventionalimmune-suppressing agent for use according to the invention includeAmphotericin, Busulphan, Co-trimoxazole, Chlorambucil, colonystimulating factors, corticosteroids, Cyclophosphamide, Fluconazole,folinic acid, Ganciclovir, antilymphocyte immunoglobulins, normalimmunoglobulins, Methotrexate, Methylprednisolone, Octreotide,Oxpentifylline, Tacrolimus (FK506), Thalidomide, Zolimomab aritox, orthe calcineurin inhibitors (protein phosphatase 2B inhibitors), inparticular Cyclosporin.

Conditions which may benefit from this treatment include, but are notlimited to diseases, disorders or conditions such as auto-immunediseases, e.g. Addison's disease, alopecia areata, Ankylosingspondylitis, haemolytic anemia (anemia haemolytica), pernicious anemia(anemia perniciosa), aphthae, aphthous stomatitis, arthritis,arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis,aspermiogenese, asthma bronchiale, auto-immune asthma, auto-immunehemolysis, Bechet's disease, Boeck's disease, inflammatory boweldisease, Burkitt's lymphoma, Chron's disease, chorioiditis, colitisulcerosa, Coeliac disease, cryoglobulinemia, dermatitis herpetiformis,dermatomyositis, insulin-dependent type I diabetes, juvenile diabetes,idiopathic diabetes insipidus, insulin-dependent diabetes mellisis,auto-immune demyelinating diseases, Dupuytren's contracture,encephalomyelitis, encephalomyelitis allergica, endophthalmiaphacoanaphylactica, enteritis allergica, auto-immune enteropathysyndrome, erythema nodosum leprosum, idiopathic facial paralysis,chronic fatigue syndrome, febris rheumatica, glomerulo nephritis,Goodpasture's syndrome, Graves' disease, Hamman-Rich's disease,Hashimoto's disease, Hashimoto's thyroiditis, sudden hearing loss,sensoneural hearing loss, hepatitis chronica, Hodgkin's disease,haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, iritis,leucopenia, leucemia, lupus erythematosus disseminatus, systemic lupuserythematosus, cutaneous lupus erythematosus, lymphogranuloma malignum,mononucleosis infectiosa, myasthenia gravis, traverse myelitis, primaryidiopathic myxedema, nephrosis, ophthalmia symphatica, orchitisgranulomatosa, pancreatitis, pemphigus, pemphigus vulgaris,polyarteritis nodosa, polyarthritis chronica primaria, polymyositis,polyradiculitis acuta, psoreasis, purpura, pyoderma gangrenosum,Quervain's thyreoiditis, Reiter's syndrome, sarcoidosis, ataxicsclerosis, progressive systemic sclerosis, scleritis, sclerodermia,multiple sclerosis, sclerosis disseminata, acquired spenic atrophy,infertility due to antispermatozoan antobodies, thrombocytopenia,idiopathic thrombocytopenia purpura, thymoma, acute anterior uveitis,vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated diseasessuch as Sjorgren's syndrome, virus (AIDS or EBV) associated B celllymphoma, parasitic diseases such as Lesihmania, and immunosuppresseddisease states such as viral infections following allografttransplantations, graft vs. Host syndrome, transplant rejection, orAIDS, cancers, chronic active hepatitis diabetes, toxic chock syndrome,food poisoning, and transplant rejection.

It is at present contemplated that a suitable dosage of the activepharmaceutical ingredient (API) is within the range of from about 0.1 toabout 1000 mg API per day, more preferred of from about 10 to about 500mg API per day, most preferred of from about 30 to about 100 mg API perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication considered, the subject andin particular the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed. These examples demonstrate general methodsfor the synthesis of the preferred compounds in this invention, and somepreferred methods for synthesis of certain embodied compounds.

2-[Bis-(4-fluoro-phenyl)-(4-nitro-3-trifluoromethyl-phenoxy)-methyl]-thiazole(Compound 1)

A solution of thiazole (2.6 g) in THF (20 ml) at −78° C. under nitrogenwas treated with 2.5M n-BuLi (12.25 ml) over 15 min. After stirring for30 min a solution of p-fluorobenzophenone (6.54 g) in THF (20 ml) wasadded and stirring continued overnight with gradual warming to roomtemperature. The reaction was quenched with sat. aq. NH₄Cl and extractedwith ethyl ether (3×). Drying (MgSO₄), filtration and concentrationafforded the carbinol as a solid (8.5 g, m.p.=88.6–89.5° C.). Thismaterial (0.5 g) was dissolved in DMF (5 ml) and treated with NaH (60%dispersion in paraffin, 76 mg). After stirring for 45 min at roomtemperature 5-fluoro-2-nitrobenzotrifluoride (0.44 g) was added and thereaction heated to 60° C. After 5 days the reaction was quenched withsat. aq. NH₄Cl and extracted with ethyl ether (3×). Drying of thecombined organic layers (MgSO₄), filtration, concentration and flashchromatography afforded the title compound (9%; M.p. 133–134° C.).

2-[(2-Fluoro-phenyl)-bis-(4-fluoro-phenyl)-methoxy]-[1,3,2]-dioxaphospholane(Compound 2)

o-Fluorophenyl-di-p-fluorophenylmethanol (628 mg) dissolved in drytoluene (10 ml) was treated with 2-chloro-1,3,2-dioxaphospholane (292mg) and refluxed for 10 hrs. The toluene was evaporated and the cruderesidue was purified by flash column chromatography to afford 260 mg ofthe title compound (32%; M.p. 163–164° C.).

2-[Tris-(4-fluoro-phenyl)-methoxy]-[1,3,2]-dioxaphospholane (Compound 3)was prepared in similar fashion in 14% yield, m.p. 195–196° C.

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-enenitrile (Compound 4)

o-Fluorophenyl-p-fluorophenylacetonitrile (1.0 g) was dissolved in dryDME (5 ml) and treated with NaH (60% dispersion in paraffin, 190 mg).After stirring for 30–45 min. at room temperature allyl bromide (0.8 g)was added and stirring continued overnight. The reaction was quenchedwith sat. aq. NH₄Cl and extracted with ethyl acetate (3×). Drying of thecombined organic layers (MgSO₄), filtration, concentration and flashchromatography afforded the title compound (39%; M.p. 215–219° C.).

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-3-methyl-butyronitrile (Compound5) was prepared in similar fashion in 47% yield, isolated as an oil.

2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyronitrile (Compound 6) wasprepared in similar fashion in 52% yield, isolated as an oil.

2,2-Bis-(4-fluoro-phenyl)-4-methyl-pentanenitrile (Compound 7) wasprepared in similar fashion in 65% yield, isolated as an oil.

2,2-Bis-(4-fluoro-phenyl)-pent-4-enenitrile (Compound 8) was prepared insimilar fashion in 70% yield, isolated as an oil.

2,2-Bis-(4-fluoro-phenyl)-pent-4-ynenitrile (Compound 9) was prepared insimilar fashion in 62% yield, m.p. 59.7–60.5° C.

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-ynenitrile (Compound 10)was prepared in similar fashion in 33% yield, isolated as an oil.

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-4-methyl-pentanenitrile(Compound 11) was prepared in similar fashion in 79% yield, isolated asan oil.

2,2-Bis-(4-fluoro-phenyl)-3,3-diphenyl-propionitrile (Compound 12) wasprepared in similar fashion in 84% yield, m.p. 208–212.5° C.

2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-3,3-diphenyl-propionitrile(Compound 13) was prepared in similar fashion in 76% yield, m.p.210–215.3° C.

2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-3-methyl-butyronitrile (Compound14) was prepared in similar fashion in 65% yield, isolated as an oil.

2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-4-methyl-pentanenitrile(Compound 15) was prepared in similar fashion in 51 % yield, isolated asan oil.

2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-enenitrile (Compound 16)was prepared in similar fashion in 72% yield, isolated as an oil.

2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-ynenitrile (Compound 17)was prepared in similar fashion in 73% yield, isolated as an oil.

2,2-Bis-(4-fluoro-phenyl)-3-oxo-butyronitrile (Compound 18) was preparedin similar fashion in 38% yield, m.p. <50° C.

2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyramide (Compound 19)

2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyronitrile (2.21 g) was suspendedin acetic acid (2 ml) and conc. sulphuric acid (2 ml) and heated to 130°C. for 1.5 hrs. The reaction mixture was poured onto ice/water and thepH adjusted to 9 with aq. ammonium hydroxide. The mixture was extractedwith dichloromethane (3×), washed with water (2×) and brine, dried(MgSO₄), filtered and concentrated. The product was taken up indichloromethane and triturated with cold hexane to precipitate the titlecompound (50%; M.p. 142.3–147.0° C.).

3-Ethoxy-2-(4-fluoro-phenyl)-2-(2-fluoro-phenyl)-propionitrile (Compound20)

A solution of o-fluorophenyl-p-fluorophenylacetonitrile (1.7 g) in THF(10 ml) was treated with sodium hydride (60% dispersion in paraffin)(0.2 g) under Argon. To the formed suspension, chloromethyl ethyl ether(0.8 g) was added dropwise and the reaction mixture was stirred at roomtemperature overnight. The mixture was filtered and concentrated. Flashchromatography of the residue afforded the title compound (1.1 g;Isolated as an oil).

3-Ethoxy-2,2-bis-(4-fluoro-phenyl)-propionitrile (Compound 21) wasprepared in similar fashion in 80% yield fromdi-p-fluorophenylacetonitrile and chloromethyl ethyl ether, isolated asan oil.

Cyano-(4-fluoro-phenyl)-(2-fluoro-phenyl)-acetic acid methyl ester(Compound 22) was prepared in similar fashion in 23% yield fromo-fluorophenyl-p-fluorophenylacetonitrile and methyl chloroformate, m.p.104–105° C.

2,2-Bis-(4-fluoro-phenyl)-3-(2-methoxy-ethoxy)-propionitrile (Compound23) was prepared in similar fashion in 70% yield fromdi-p-fluorophenylacetonitrile and MEM-chloride, isolated as an oil.

2,2-Bis-(4-fluoro-phenyl)-succinonitrile (Compound 24) was prepared insimilar fashion in 38% yield from di-p-fluorophenylacetonitrile andchloroacetonitrile, m.p. 93–94° C.

3-Cyano-3-(4-fluoro-phenyl)-3-(2-fluoro-phenyl)-propionic acid ethylester (Compound 25)

A solution of o-fluorophenyl-p-fluorophenylacetonitrile (1.7 g) inethylmethyl ketone (10 ml) was treated with potassium carbonate (2 g)and potassium iodide (0.1 g). To the formed suspension, ethylbromoacetate (2 g) was added dropwise and the reaction mixture wasrefluxed overnight. The mixture was filtered and concentrated. Flashchromatography of the residue afforded the title compound (1.4 g;Viscous gum).

3-Cyano-3,3-bis-(4-fluoro-phenyl)-propionic acid ethyl ester (Compound26) was prepared in similar fashion in 61% yield usingdi-p-fluorophenylacetonitrile and ethyl bromoacetate, isolated as anoil.

2-[Cyano-bis-(4-fluoro-phenyl)-methyl]-malonic acid diethyl ester(Compound 27)

To THF (80 ml) were added sequentially, a 1.0 M solution of TiCl₄ indichloromethane (80 ml), p,p′-difluorobenzophenone (8.73 g) and diethtylmalonate (6.4 g) in THF 20 ml. After stirring at 0° C. for 40 min, asolution of pyridine (12.8 ml) in THF (28 ml) was added dropwise. Theensuing mixture was stirred for 4 days. The reaction was quenched withwater and diethyl ether. The aqueous phase was separated and extractedtwice more with diethyl ether. The combined organic phases were washedwith brine, sat. sodium bicarbonate solution and again with brine.Drying of the organic phase (MgSO₄), filtration and concentrationafforded a residue from which residual diethyl malonate was removed byKugelrohr destillation. The residue was flash chromatographed to provide1,1-di-p-fluorophenyl-2,2-di-ethoxycarbonylethylene (25%, m.p.=117–119°C.). To this product (5.9 g) were added ammonium chloride (1.31 g), KCN(2.18 g), DMF (175 ml) and water (22 ml) and the mixture was heated to100° C. for 8 hrs. The cooled reaction mixture was poured into water andextracted (3×) with ethyl ether. The combined organic phases were washedwith water, aq. 2N HCl, aq. 5% NaHCO₃ and brine. Drying (Na₂SO₄),filtration and evaporation of volatiles gave a residue which wasrecrystallised from ether-hexane to afford the title compound (56%; M.p.90–91° C.).

2,2-Bis-(4-fluoro-phenyl)-4-hydroxy-butyronitrile (Compound 28)

Ethylene glycol dimethyl ether (10 ml) was treated with sodiumborohydride (142 mg) and LiCl (228 mg) and the mixture stirred for 30min. 3-Cyano-3,3-bis-(4-fluoro-phenyl)-propionic acid ethyl ester (847mg) was added and the mixture stirred for 6 hrs, before more sodiumborohydride (36 mg) and LiCl (57 mg) were added and stirring continuedovernight. The mixture was poured into water and extracted (3×) withethyl ether. The combined organic extracts were dried over Na₂SO₄.Filtration, concentration and flash chromatography of the residueafforded the title compound (41%; Isolated as an oil).

General Method for the Preparation of Compound Type 1 Synthesis of TriSubstituted Methanole:

A solution of a substituted benzene (2.5 equivalent) and aluminumchloride (5 equivalent) in dry carbon disulfide (0.5 L/mol) is heated togentle reflux. An arylcarbonylchloride (2 equivalent) is added slowlyfrom a dropping funnel. After 1 hour the addition is completed and thegentle reflux is continued for another hour. The dropping funnel isremoved, a condenser is attached and carbon disulfide is distilled. Thereaction mixture is poured slowly over a mixture of cracked ice andhydrochloric acid. The aqueous phase is extracted twice with toluene,the extract are combined and washed with water, aqueous sodium hydroxideand dried over sodium sulfate. Evaporation of the solvent gave thephenyl-aryl ketone in 69–90% yield.

The substituted phenyl-aryl ketone is added drop-wise to a refluxingsolution of a Grignard Reagents in ether. After 3 hours the reactionmixture is cooled and poured into water. The aqueous phase is extractedtwice with methylene chloride and the combined organic phases is driedwith sodium sulfate, filtrated and the solvent evaporated. The crudeproduct are crystallized or purified by column chromatography to givetrisubstitutedmethanoles in 73–90% yield.

General Method for the Preparation of Compound Type 2 Synthesis of TriSubstituted Chloromethane:

A solution of a compound Type 1 in methylene chloride (2 mL/mmol) isheated to gentle reflux. Thionylchloride (2 equivalent) is added from adropping funnel during 15 minutes and the reflux is continued foranother 1 hour. Excess thionylchloride and methylene chloride is removedby evaporation. Toluene is added twice, and evaporated to afford crudetri substituted chloromethane in 95–100% yield. This product was usedwithout purification in the next step.

General Method for the Preparation of Compound Type 3 Synthesis of TriSubstituted Methyl Mercaptane:

A solution of a compound Type 1 in toluene is heated to gentle refluxwith 2,4-bis(p-methoxyphenyl)-1,3-dithiaphosphetane-2,4-disulphide for 1hour. Toluene is removed by evaporation and the crude product ispurified by column chromatography affording tri substituted methylmercaptane in 90–100% yield.

General Method for the Preparation of Compound Type 4 Synthesis of TriSubstituted Methyl Carbamates

A compound Type 1 is dissolved in dichloromethane (DCM) (3 mL/mmol),pyridine (1 equivalent) and 4-nitrophenyl chloroformate (1 equivalent)are added and the solution is heated to refluxed for 3 hour. Thereaction mixture is cooled washed with aq hydrochloric acid, 10% sodiumcarbonate and water. Dried with magnesium sulfate, filtrated and thesolvent removed under reduced pressure. The crude product is purified bycolumn chromatography affording substituted carbonate in 77–86% yield.

The substituted carbonate is dissolved in dimethoxyethane (DME) (3mL/mmol), and the amine is added (1 equivalent) together with4-dimethylaminopyridine (DMAP) (1 equivalent). The reaction mixture isheated for 14 hours at 50° C., cooled to room temperature, washed withaq hydrochloric acid, 10% sodium carbonate and water. Dried withmagnesium sulfate, filtrated and the solvent removed under reducedpressure. The crude product is purified by column chromatographyaffording substituted carbamate in 74–80% yield.

In this way the following tri substituted methyl carbamates areobtained:

(±)-Carbamic acid tris-(4-fluorophenyl)-methyl ester (Compound 4-1);

(±)-Carbamic acid cyclohexyl-bis-(4-fluorophenyl)-methyl ester (Compound4-2);

(±)-Carbamic acid cyclohexyl-(4-fluorophenyl)-thiazol-2-yl-methyl ester(Compound 4-3);

(±)-Piperidine-1-carboxylic acidtris-(4-fluorophenyl)-thiazol-2-yl-methyl ester (Compound 4-4);

(±)-Methyl-carbamic acid cyclopentyl-bis-(4-fluorophenyl)-methyl ester(Compound 4-5);

(±)-Pyrrolidine-1-carboxylic acid cyclohexyl-bis-(4-fluorophenyl)-methylester (Compound 4-6);

(±)Methyl-carbamic acid tris-(4-fluorophenyl)-methyl ester (Compound4-7);

(±)-Methyl-carbamic acidcyclohexyl-(2-fluorophenyl)-(4-fluorophenyl)-methyl ester (Compound4-8);

(±)-Carbamic acid cyclohexyl-(4-fluorophenyl)-pyridin-2-yl-methyl ester(Compound 4-9);

(±)-Dimethyl-carbamic acid tris-(4-fluorophenyl)-methyl ester (Compound4-10);

(±)-Carbamic acid (2-fluorophenyl)-bis-(4-fluorophenyl)-methyl ester(Compound 4-11); and

(±)-Carbamic acid (2-fluorophenyl)-(4-fluorophenyl)-phenyl-methyl ester(Compound 4-12).

General Method for the Preparation of Compound Type 5 Synthesis of TriSubstituted Methyl Sulfide

Magnesium tunings in anhydrous diethyl ether is heated to gentle reflux,and a solution of compound Type 2 (1 equivalent) in anhydrous diethylether is added slowly from a dropping funnel at such a rate that gentlereflux continue without further heating. When the addition is completed,the reaction mixture is heated to gentle reflux until only traces ofunreacted magnesium remains. The reaction mixture is cooled in an icebath, and finely powered sulfur (1 equivalent) is added and the reactionis heated to gentle reflux for another 1 hour. (OBS! A vigorous reactionwith sulfur takes place when the reaction is heated for reflux).

The reaction mixtures is cooled again on the ice bath, alkyl bromide(1.1 equivalent) is added dropwise from the funnel, and the mixture isheated for reflux 16 hours then cooled. DCM is added and the reactionmixture is washed twice with 5% sodium hydroxide and twice with water.Dried with magnesium sulfate, filtrated and the solvent removed underreduced pressure. The crude product is purified by column chromatography(hexane:DCM) affording sulfide Type 5 in 60–84% yield.

In this way the following tri substituted methyl sulfides are obtained:

2-[Cyclohexyl-(4-fluorophenyl)-(2-fluorophenyl)-methylsulfanyl]-thiazole(Compound 5-1);

2-[(2-Chlorophenyl)-cyclohexyl-(4-fluorophenyl)-(2-fluorophenyl)-methylsulfanyl]-1-methyl-1H-imidazole(Compound 5-2);

2-[(4-Chlorophenylsulfanyl)-cyclopentyl-(4-fluorophenyl)-(2-fluorophenyl)-methyl]-pyridine(Compound 5-3);

2-[Cyclohexyl-(3,4-dichlorophenyl)-(1H-imidazol-2-yl)-methylsulfanyl]-pyridine(Compound 5-4);

2-[Cyclopentyl-(2-fluorothiazol-4-yl)-(4-nitro-3-trifluoromethylphenyl)-methylsulfanyl]-pyridine (Compound5-5);

2-[(4-fluorophenyl)-(4-fluorophenylsulfanyl)-(4-nitro-3-trifluoromethylphenyl)-methyl]-thiazole(Compound 5-6);

2-[Cyclohexylsulfanyl-(4-fluorophenyl)-(4-nitro-3-trifluoromethylphenyl)-methyl]-thiazole(Compound 5-7);

2-[Cyclopentylsulfanyl-bis-(4-fluorophenyl)-methyl]-1-methyl-1H-imidazole(Compound 5-8);

4-[Cyclohexylsulfanyl-bis-(4-fluorophenyl)-methyl]-2-fluoro-thiazole(Compound 5-9);

2-[Bis-(4-fluorophenyl)-(2-fluorophenyl)-methylsulfonyl]-thiazole(Compound 5-10);

1-Methyl-2-[tris-(4-fluorophenyl)-methylsulfanyl]-1H-imidazole (Compound5-11); Mp. 135.5–140.5° C.;

2-[Tris-(4-fluorophenyl)-methylsulfanyl]-pyridine (Compound 5-12);isolated as an oil; and

2-[Tris-(4-fluorophenyl)-methylsulfanyl]-pyridine-N-oxide (Compound5-13); Mp. 147.7–151.8° C.

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-N,N-diethyl-acetamide(Compound 5-14)

Metallic sodium (1 mmol) was dissolved in dry methanol (8 ml) ando-fluorophenyl-di-p-fluorophenylmethyl sulfide (0.91 mmol) was added atroom temperature under Argon. After stirring for 15 min, N,N-diethylchloroacetamide (1 mmol) was added dropwise. After stirring for anotherhour at room temperature the reaction mixture was poured into water.Extraction with diethyl ether (3×), drying with sodium sulfate,filtration and concentration gave a residue, which wasflash-chromatographed to afford the title compound as a white solid(52%; M.p. 122–123° C.).

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-N-methyl-N-Phenyl-acetamide(Compound 5-15) was prepared in similar fashion in 43% yield usingN-methyl-N-phenyl chloroacetamide, m.p. 120–121° C.

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-1-piperidin-1-yl-ethanone(Compound 5-16) was prepared in similar fashion in 42% yield usingpiperidinyl chloroacetamide, m.p. 128–129° C.

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-acetamide(Compound 5-17) was prepared in similar fashion in 63% yield usingiodoacetamide, THF as solvent and K₂CO₃ as base, m.p. 119–120° C.

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-propionamide(Compound 5-18) was prepared in similar fashion in 28% yield usingacrylamide, m.p. 133–134° C.

[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-acetonitrile(Compound 5-19)

A solution of chloroacetonitrile (5.45 mmol) was added dropwise to astirring mixture of o-fluorophenyl-di-p-fluorophenylmethyl sulfide (4.54mmol) and potassium carbonate (9.1 mmol) in THF (20 ml) at roomtemperature under Argon. After stirring for 2.5 hours at roomtemparature, 3.5 hours at 40° C. and 2 hours at 60° C. the mixture waspoured into ice-cold water. Extraction with ethyl ether (3×), drying ofthe combined organic extracts (Na₂SO₄), filtration, concentration andflash-chromatography of the residue gave the title compound (41 %; M.p.111–112° C.).

[(2-Fluoro-phenyl)-bis-(4-fluoro-phenyl)-methylsulfanyl]-acetic acid(Compound 5-20)

A solution of di-p-fluorophenyl-o-fluorophenylcarbinol (0.2 g) wasdissolved in trifluoroacetic acid (3 ml) and treated with mercaptoaceticacid (0.5 ml) at room temperature. After stirring for 4 hours at roomtemperature the reaction was poured into water. Extraction with ethylether (3×), drying of the combined organic extracts (Na₂SO₄),filtration, concentration and flash-chromatography of the residue gavethe title compound (69%; M.p. 112–113° C.).

2-[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-thioacetamide(Compound 5-21)

A solution of2-[bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-acetamide(0.5 g) in toluene (20 ml) was treated with Lawesson's reagent (0.26 g)at room temperature under Argon and stirred for 1.5 hours at 80° C.After pouring into saturated brine the organics were extracted withdichloromethane (3×). Drying of the combined organic extracts (Na₂SO₄),filtration, concentration and flash-chromatography of the residue gavethe title compound (42%; Isolated as an oil).

General Method for the Preparation of Compound Type 6 Synthesis of TriSubstituted Methyl Sulfoxide

A compound Type 5 is dissolved in dichloromethane (DCM) (3 mL/mmol),cooled to −5° C., and 3-chloroperoxybenzoic acid (MCPBA) (1.0equivalent) is added in small portions over 30 minutes. After 30 minutesat room temperature the reaction mixture is poured into water andextracted with DCM, dried with magnesium sulfate, filtrated and thesolvent removed under reduced pressure. The crude product is purified bycolumn chromatography (benzin:ethyl acetate) affording a compound Type 6in 80–95% yield.

In this way the following tri substituted methyl sulfoxides areobtained:

Methyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-1);

Ethyl (bis(4-fluorophenyl)phenyl)methyl sulfoxide (Compound 6-2);

Cyclohexylmethyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-3);

Cyclohexyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-4);

Isopropyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-5);

(2-Thiazolyl)methyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-6);

Phenyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-7);

1-Methyl-2-imidazolyl tris(4-fluorophenyl)methyl) sulfoxide (Compound6-8);

2-Pyridyl tris(4-fluorophenyl)methyl sulfoxide (Compound 6-9);

(Cyclohexyl-bis(4-fluorophenyl))methyl phenyl sulfoxide (Compound 6-10);

(Cyclopentyl-bis(4-fluorophenyl))methyl methyl sulfoxide (Compound6-11); and

(Cyclohexyl-(4-fluorophenyl)-(2-thiazolyl))methyl methyl sulfoxide(Compound 6-12).

General Method for the Preparation of Compound Type 7 Synthesis ofSulfone

To a solution of a compound Type 2 and a sodium sulphinate (1.5equivalent) in dimethyl sulfoxide (DMSO) (2 mL/mmol) is heated to 60° C.for 4 hours. The reaction mixture is poured into water, extracted withdiethyl ether, dried with sodium sulfate, filtrated and the solventremoved under reduced pressure to give 80–88% yield. The crude productis purified by crystallization from acetic acid to give 45–55% yield.

In this way the following sulfones are obtained:

Methyl tris(4-fluorophenyl)methyl sulfone (Compound 7-1); Mp.140.6–145.3° C.;

Ethyl (bis(4-fluorophenyl)phenyl)methyl sulfone (Compound 7-2);

Cyclohexylmethyl tris(4-fluorophenyl)methyl sulfone (Compound 7-3);

Cyclohexyl tris(4-fluorophenyl)methyl sulfone (Compound 7-4);

Isopropyl tris(4-fluorophenyl)methyl sulfone (Compound 7-5);

(2-Thiazolyl)methyl tris(4-fluorophenyl)methyl sulfone (Compound 7-6);

Phenyl tris(4-fluorophenyl)methyl sulfone (Compound 7-7); Mp.157.4–160.6° C.;

1-Methyl-2-imidazolyl tris(4-fluorophenyl)methyl) sulfone (Compound7-8);

2-Pyridyl tris(4-fluorophenyl)methyl sulfone (Compound 7-9);

(Cyclohexyl-bis(4-fluorophenyl))methyl phenyl sulfone (Compound 7-10);

(Cyclopentyl-bis(4-fluorophenyl))methyl methyl sulfone (Compound 7-11);

(Cyclohexyl-(4-fluorophenyl)-(2-thiazolyl))methyl methyl sulfone(Compound 7-12);

((2-Fluorophenyl)-bis(4-fluorophenyl)-phenyl)methyl methyl sulfone(Compound 7-13); and

Methanesulphonyl-2-fluorophenyl-bis-(4-fluoro-phenyl) methane (Compound7-14); (76%; M.p. 147–149° C.).

General Method for the Preparation of Compound Type 8 Synthesis ofSulfin Amides

Magnesium tunings in anhydrous diethyl ether is heated to gentle reflux,and a solution of compound Type 2 (1 equivalent) in anhydrous diethylether is added slowly from a dropping funnel at such a rate that gentlereflux continue without further heating. When the addition is completed,the reaction mixture is heated to gentle reflux until only traces ofunreacted magnesium remains. This Grignard reagent is used in the nextstep.

Anhydrous diethyl ether in a 3-neck flask is cooled in an acetone/CO₂bath. The flask is fitted with a SO₂ inlet adaptor, a dropping funnelwith the Grignard reagent and an outlet gas trap with aq. NaOH.

SO₂ is condensed, in the cooled ether, by a gentle flux through theoutlet gas trap. The Grignard reagent is added drop wise from the funnelduring 1 hour.

The sulfinic acid is liberated by acidic work-up and is dissolved indichloromethane (10ml/g). Thionyl chloride (1 equivalent) is added andthe mixture is heated to reflux until the evolution of gasses ceases.The reaction mixture is cooled in an ice bath and a solution of theappropriate amine (2 equivalents) in dichloromethane is added. Theresulting mixture is stirred at ambient or elevated temperature untilcompletion of the reaction.

In this way the following sulfin amides are obtained:

-   -   Tris-(4-fluorophenyl)-methanesulfinic acid amide (Compound 8-1);    -   Bis-(4-fluorophenyl)-phenyl-methanesulfinic acid methylamide        (Compound 8-2);    -   Tris-(4-fluorophenyl)-methanesulfinic acid cyclohexylamide        (Compound 8-3);    -   1-[Tris-(4-fluorophenyl)-methanesulfinyl]-piperidine (Compound        8-4);    -   Tris-(4-fluorophenyl)-methanesulfinic acid dimethylamide        (Compound 8-5);    -   Tris-(4-fluorophenyl)-methanesulfinic acid thiazol-2-ylamide        (Compound 8-6);    -   Tris-(4-fluorophenyl)-methanesulfinic acid        (4-fluorophenyl)-amide (Compound 8-7);    -   Bis-(4-fluorophenyl)-(1-methyl-1H-imidazol-2-yl)-methanesulfinic        acid methylamide (Compound 8-8);    -   Cyclohexyl-(4-fluorophenyl)-thiazol-2-yl-methanesulfinic acid        amide (Compound 8-9);    -   Bis-(4-fluorophenyl)-(1-methyl-1H-imidazol-2-yl)-methanesulfinic        acid amide (Compound 8-10);    -   Bis-(4-fluorophenyl)-thiazol-2-yl-methanesulfinic acid amide        (Compound 8-11); and    -   Bis-(4-fluorophenyl)-oxazol-2-yl-methanesulfinic acid amide        (Compound 8-12).

General Method for the Preparation of Compound Type 9 Synthesis ofThiocarbamate

A compound Type 3 is dissolved in dichloromethane (DCM) (3 mL/mmol),pyridine (1 equivalent) and 4-nitrophenyl chloroformate (1 equivalent)are added and the solution is heated to refluxed for 3 hour. Thereaction mixture is cooled washed with aq hydrochloric acid, 10% sodiumcarbonate and water. Dried with magnesium sulfate, filtrated and thesolvent removed under reduced pressure. The crude product is purified bycolumn chromatography affording substituted thiocarbonate.

The substituted thiocarbonate is dissolved in dimethoxyethane (DME) (3mL/mmol), and the amine is added (1 equivalent) together with4-dimethylaminopyridine (DMAP) (1 equivalent). The reaction mixture isheated for 14 hours at 50° C., cooled to room temperature, washed withaq hydrochloric acid, 10% sodium carbonate and water. Dried withmagnesium sulfate, filtrated and the solvent removed under reducedpressure. The crude product is purified by column chromatographyaffording substituted thiocarbamate.

In this way the following thiocarbamates are obtained:

-   -   Thiocarbamic acid S-[tris-(4-fluorophenyl)-methyl]ester        (Compound 9-1);    -   Thiocarbamic acid        S-[cyclohexyl-bis-(4-fluorophenyl)-methyl]ester(Compound 9-2);    -   Thiocarbamic acid        S-[cyclohexyl-(4-fluorophenyl)-thiazol-2-yl-methyl]ester        (Compound 9-3);    -   Piperidine-1-carbothioic acid        S-[tris-(4-fluorophenyl)-methyl]ester (Compound 9-4);    -   Methyl-thiocarbamic acid        S-[cyclopentyl-bis-(4-fluorophenyl)-methyl]ester (Compound 9-5);    -   Pyrrolidine-1-carbothioic acid        S-[cyclohexyl-bis-(4-fluorophenyl)-methyl]ester (Compound 9-6);    -   Methyl-thiocarbamic acid S-[tris-(4-fluorophenyl)-methyl]ester        (Compound 9-7);    -   Methyl-thiocarbamic acid        S-[cyclopentyl-(2-fluorophenyl)-(4-fluorophenyl)-methyl]ester        (Compound 9-8);    -   Thiocarbamic acid        S-[cyclohexyl-(4-fluorophenyl)-pyridin-2-yl-methyl] ester        (Compound 9-9);

Dimethyl-thiocarbamic acid S-[tris-(4-fluorophenyl)-methyl]ester(Compound 9-10);

Thiocarbamic acid S-[(2-fluorophenyl)-bis-(4-fluorophenyl)-methyl]ester(Compound 9-11); and

Thiocarbamic acidS-[(2-fluorophenyl)-(4-fluorophenyl)-phenyl-methyl]ester (Compound9-12).

General Method for the Preparation of Compound Type 10 Synthesis ofPhosphonate

A compound Type 2 in toluene (2 mL/mmol) and trialkyl phosphite (4equivalent) is heated at reflux for 16 hours under a nitrogenatmosphere. The reaction mixture is cooled and the volatiles are removedunder reduced pressure. The crude product is purified by columnchromatography (benzin:ethyl acetate) (20:1) or by crystallization frombenzin, affording alkyl phosphonate in 61-82% yield.

In this way the following phosphonates are obtained:

[Tris-(4-fluorophenyl)-methyl]-phosphonic acid dimethyl ester (Compound10-1); Mp. 131.6° C.;

[(2-Fluorophenyl)-bis-(4-fluorophenyl)-methyl]-phosphonic acid dimethylester (Compound 10-2); Mp. 136.6° C.;

[(3-Fluorophenyl)-bis-(4-fluorophenyl)-methyl]-phosphonic acid dimethylester (Compound 10-3);

2-[Tris-(4-fluorophenyl)-methyl]-[1,3,2]dioxaphospholane 2-oxide(Compound 10-4);

[Cyclohexyl-bis-(4-fluorophenyl)-methyl]-phosphonic acid dimethyl ester(Compound 10-5);

Cyclopentyl-bis-(4-fluorophenyl)-methyl]-phosphonic acid dipropyl ester(Compound 10-6);

[(4-Chlorophenyl)-bis-(4-fluorophenyl)-methyl]-phosphonic acid dimethylester (Compound 10-7);

[1,1-Bis-(4-fluorophenyl)-hexyl]-phosphonic acid dimethyl ester(Compound 10-8);

[1,1-Bis-(4-fluorophenyl)-2-methyl-propyl]-phosphonic acid dimethylester (Compound 10-9);

[Bis-(4-fluorophenyl)-pyridin-2-yl-methyl]-phosphonic acid dimethylester (Compound 10-10); and

[Bis-(4-fluorophenyl)-thiazol-2-yl-methyl]-phosphonic acid dimethylester (Compound 10-11).

[(2-Chloro-phenyl)-(2-fluoro-phenyl)-(4-fluoro-phenyl)-methyl]-phosphonicacid di-methyl ester (Compound 10-12)

Chloro tri-p-fluorophenylmethane (860 mg) dissolved in toluene (15 ml)was treated with trimethylphosphite (449 mg) and the reaction wasrefluxed for 6 hours. Toluene was evaporated and the crude residuepurified by flash chromatography to afford 62% of the dimethylphosphonate ester of the title compound (97%; M.p. 131,5-1 32,5° C.).

[(4-Chloro-phenyl)-bis-(4-fluoro-phenyl)-methyl]-phosphonic aciddimethyl ester (Compound 10-13)

Chloro tri-p-fluorophenylmethane (860 mg) dissolved in toluene (15 ml)was treated with trimethylphosphite (449 mg) and the reaction wasrefluxed for 6 hours. Toluene was evaporated and the crude residuepurified by flash chromatography to afford 62% of the dimethylphosphonate ester of the title compound (67%; M.p. 136-137° C.).

[Bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methyl]-phosphonic acid(Compound 10-14)

To a solution of the phosphonate[(2-Fluoro-phenyl)-bis-(4-fluoro-phenyl)-methyl]-phosphonic aciddimethyl ester (195 mg) in acetonitrile (7 ml) was addediodotrimethylsilane (0.17 ml) under Argon. The reaction mixture was leftstirring for 3 hrs and then the volatiles were evaporated. 10 ml each ofwater and chloroform were added to the residue and the mixture wasstirred for a further 30 min. The organic phase was separated and thewater layer was extracted twice more with CHCl₃. Drying of the combinedorganic extracts with MgSO₄, filtration, concentration andrecrystallisation of the residue from acetonitrile afforded a whitesolid (100 mg; M.p. 228-230° C.).

[Bis-(4-fluoro-phenyl)-p-tolyl-methyl]-phosphonic acid (Compound 10-15)was prepared in similar fashion in 72% yield, m.p. 240° C. (decomposes).

General Method for the Preparation of Compound Type 11 Synthesis ofPhosphonate

A substituted benzoyl chloride is cooled to 10° C. and trialkylphosphite (1.1 equivalent) is added slowly from a dropping funnel during2 hours, with vigorous stirring under nitrogen. An exothermic reactionwith evolution of alkyl chloride gas takes place, and the reactiontemperature is maintained below 30° C. (ice/water bath). The reaction iscompleted at room temperature for 3–5 hours with a gentle flux ofnitrogen, and then distilled at reduced pressure (10⁻² Torr) to givesubstituted dialkyl benzoylphosphonates in 69–95% yield.

The substituted dialkyl benzoylphosphonates prepared as described aboveis added to a fresh prepared Grignard reagent (1.1 equivalent) in etherat −78° C. After 15 minutes the reaction mixture is poured into 0.1 MHCl, extracted with diethyl ether, dried with sodium sulfate, filtratedand the solvent removed under reduced pressure to give crude product.The crude product is purified by column chromatography (benzin:ethylacetate) or by crystallization from benzin, affording Type 11 compoundin 45–60% yield.

General Method for the Preparation of Compound Type 12 Synthesis ofPhosphonate

A compound of Type 11 is deprotonated by treatment with sodium hydride(1 equivalent) in dichloromethane. The resulting alcoholate ion isalkylated by treatment with the appropriate alkyl halide under standardconditions.

In this way the following phosphonates are obtained:

[Bis-(4-fluorophenyl)-isopropoxy-methyl]-phosphonic acid dimethyl ester(Compound 12-1);

[(2-Fluorophenyl)-(4-fluorophenyl)-isobutoxy-methyl]-phosphonic aciddimethyl ester (Compound 12-2); and

2-[Bis-(4-fluorophenyl)-isopropoxy-methyl]-[1,3,2]-dioxaphospholane2-oxide (Compound 12-3).

1. A compound according to Formula I

or any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, wherein L¹, L², and L³ areabsent; X and Y both represent a phenyl group, which phenyl group issubstituted with halogen; Z represents alkyl, alkenyl, alkynyl, orcycloalkyl; and D represents —CN, R⁶—CN, or —CON(R²R³), wherein R² andR³, independently of each another, represent hydrogen or alkyl; and R⁶represents alkyl.
 2. The compound of claim 1, which is2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-enenitrile;2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-3-methyl-butyronitrile;2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyronitrile;2,2-Bis-(4-fluoro-phenyl)-4-methyl-pentanenitrile;2,2-Bis-(4-fluoro-phenyl)-pent-4-enenitrile;2,2-Bis-(4-fluoro-phenyl)-pent-4-ynenitrile;2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-ynenitrile;2-(2-Fluoro-phenyl)-2-(4-fluoro-phenyl)-4-methyl-pentanenitrile;2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-3-methyl-butyronitrile;2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-4-methyl-pentanenitrile;2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-enenitrile;2-(3-Fluoro-phenyl)-2-(4-fluoro-phenyl)-pent-4-ynenitrile; or2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyramide; or any of its enantiomersor any mixture of its enantiomers, or a pharmaceutically acceptable saltthereof.
 3. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1, or apharmaceutically-acceptable addition salt thereof, together with atleast one pharmaceutically-acceptable carrier or diluent.
 4. Thecompound of claim 1, wherein X and Y both represent a phenyl groupsubstituted with fluoro or chloro.
 5. The compound of claim 1, wherein Xand Y both represent a phenyl group substituted with fluoro.
 6. Thecompound of claim 1, wherein Z represents alkyl.
 7. The compound ofclaim 1, wherein D represents —CN.
 8. The compound of claim 1, wherein Drepresents —CON(R²R³), wherein R² and R³, independently of each another,represent hydrogen or alkyl.
 9. The compound of claim 1, wherein Drepresents —CON(R²R³), wherein R² and R³ hydrogen.
 10. The compound ofclaim 1, which is 2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyronitrile, or apharmaceutically acceptable salt thereof.
 11. The compound of claim 1,which is 2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyramide, or apharmaceutically acceptable salt thereof.